Dihydropyridone amides as p2x7 modulators

ABSTRACT

Compounds of the formula I: 
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salts thereof, wherein m, n, p, q, R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of diseases associated with the P2X7 purinergic receptor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is entitled to the benefit of U.S. ProvisionalApplication Ser. No. 61/203,462, filed Dec. 23, 2008, the disclosure ofwhich is incorporated herein by reference.

FIELD OF THE INVENTION

This invention pertains to compounds useful for treatment of diseasesassociated with P2X purinergic receptors, and more particularly to P2X₇modulators usable for treatment of autoimmune and inflammatory diseases.

BACKGROUND OF THE INVENTION

P2X purinergic receptors are ATP-activated ionotropic receptors havingseven subtypes. The P2X7 receptor subtype (also known as the P2Zreceptor) is a ligand-gated ion channel found on mast cells, peripheralmacrophages, lymphocytes, erythrocytes, fibroblasts and epidermallangerhans cells. Activation of P2X7 receptor on such immune systemcells results in release of interleukin-1beta. (Solle et al., J. Biol.Chemistry 276, 125-132, (2001)). The P2X7 receptor is also found onmicroglia, Schwann cells and astrocytes within the central nervoussystem (Donnelly-Roberts et al., Br. J. Pharmacol. 151, 571-579 (2007)).

Antagonists of P2X7 have been showned to block P2X7-mediated IL-1betarelease and P2X7-mediated cation flux (Stokes et al., Br. J. Pharmacol.149, 880-887 (2006)). Mice lacking the P2X7 receptor show a lack ofinflammatory and neuropathic hypersensitivity to mechanical and thermalstimuli (Chessell et al., Pain 114, 386-396 (2005)). P2X7 is thusbelieved to have a role in inflammatory responses (Ferrari et al., J.Immunol. 176, 3877-3883 (2006)) and in the onset and persistence ofchronic pain (Honore et al., J. Pharmacol. Ex. Ther. 319, 1376-1385(2006b)).

Modulators of the P2X7 receptor thus may have utility in the treatmentof disease states such as rheumatoid arthritis, osteoarthritis,psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonarydisease, airways hyper-responsiveness, septic shock, glomerulonephritis,irritable bowel disease, diabetes and Crohn's disease. P2X7 modulatorsmay also be useful for treatment of pain, including chronic pain,neuropathic pain, and pain associated inflammatory processes anddegenerative conditions.

There is accordingly a need for compounds that act as modulators of P2Xreceptors, including antagonists of P2X₇ receptor, as well as a need formethods of treating diseases, conditions and disorders mediated by P2X₇The present invention satisfies these needs as well as others.

SUMMARY OF THE INVENTION

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof,wherein:

m is 0 or 1;

n is 0 or 1;

p is from 0 to 4;

q is 0 or 1;

R¹ is:

-   -   hydrogen;    -   C₁₋₆alkyl;    -   hydroxy-C₁₋₆alkyl;    -   C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy C₁₋₆alkoxy-C₁₋₆alkyl; or    -   aminocarbonyl-C₁₋₆alkyl;

R² is:

-   -   optionally substituted aryl;    -   optionally substituted heteroaryl;    -   C₃₋₆cycloalkyl; or    -   C₁₋₆alkyl; and

R³ is:

-   -   hydrogen;    -   C₁₋₆alkyl;    -   alkylcarbonylalkyl; or    -   alkoxycarbonylalkyl;

R⁴ and R⁵ each independently is:

-   -   hydrogen; or    -   C₁₋₆alkyl;

each R⁶ is independently: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl;halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfanyl;C₁₋₆alkylsulfinyl; phenylsulfonyl wherein the phenyl portion isoptionally substituted with C₁₋₆alkyl; nitrile; hydroxy;C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkoxycarbonyl;C₁₋₆alkoxycarbonyl-C₁₋₆alkoxy; hydroxycarbonyl;hydroxycarbonyl-C₁₋₆alkoxy; C₁₋₆alkylaminocarbonyl-C₁₋₆alkoxy;C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylamino-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkoxy; amino; amino-C₁₋₆alkyl; C₁₋₆alkenyl;C₁₋₆alkynyl; morpholinyl; morpholinyl-C₁₋₆alkyl; piperazinyl;piperidinyloxy; aminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxyamino-C₁₋₆alkyl;hydroxy-C₁₋₆alkylamino-C₁₋₆alkyl; C₁₋₆alkoxycarbonylamino-C₁₋₆alkyl;C₁₋₆alkylcarbonylamino-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl;C₁₋₆alkoxycarbonylC₁₋₆alkyl; C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl;C₁₋₆alkylamino-C₁₋₆alkyl; hydroxycarbonyl-C₁₋₆alkyl; hydroxyC₁₋₆alkoxy-C₁₋₆alkyl; or nitro; or two adjacent substituents may form aC₁₋₂alkylenedioxy or halo-C₁₋₂alkylenedioxy; and

A is a five or six membered heteroaryl ring that is optionallysubstituted.

The invention also provides and pharmaceutical compositions comprisingthe compounds, methods of using the compounds, and methods of preparingthe compounds.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

“Alkyl” means the monovalent linear or branched saturated hydrocarbonmoiety, consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms. “Lower alkyl” refers to an alkyl group of one tosix carbon atoms, i.e. C₁-C₆alkyl. Examples of alkyl groups include, butare not limited to, methyl, ethyl, propyl, isopropyl, isobutyl,sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl,propenyl, and the like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one triple bond, e.g., ethynyl,propynyl, and the like.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

“Alkoxy” and “alkyloxy”, which may be used interchangeably, mean amoiety of the formula —OR, wherein R is an alkyl moiety as definedherein. Examples of alkoxy moieties include, but are not limited to,methoxy, ethoxy, isopropoxy, and the like.

“Alkoxyalkyl” means a moiety of the formula R^(a)—O—R^(b)—, where R^(a)is alkyl and R^(b) is alkylene as defined herein. Exemplary alkoxyalkylgroups include, by way of example, 2-methoxyethyl, 3-methoxypropyl,1-methyl-2-methoxyethyl, 1-(2-methoxyethyl)-3-methoxypropyl, and1-(2-methoxyethyl)-3-methoxypropyl.

“Alkoxyalkoxy’ means a group of the formula —O—R—R′ wherein R isalkylene and R′ is alkoxy as defined herein.

“Alkylcarbonyl” means a moiety of the formula —C(O)—R, wherein R isalkyl as defined herein.

“Alkoxycarbonyl” means a group of the formula —C(O)—R wherein R isalkoxy as defined herein.

“Alkylcarbonylalkyl” means a group of the formula —R—C(O)—R wherein R isalkylene and R′ is alkyl as defined herein.

“Alkoxycarbonylalkyl” means a group of the formula —R—C(O)—R wherein Ris alkylene and R′ is alkoxy as defined herein.

“Alkoxycarbonylalkoxy” means a group of the formula —O—R—C(O)—R′ whereinR is alkylene and R′ is alkoxy as defined herein.

“Alkoxy hydroxyalkyl” and “hydroxy alkoxyalkyl”, which may be usedinterchangeably, means an alkyl as defined herein that is substituted atleast once with hydroxy and at least once with alkoxy. “Alkoxyhydroxyalkyl” and “hydroxy alkoxyalkyl” thus encompass, for example,2-hydroxy-3-methoxy-propan-1-yl and the like.

“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OHwherein R is alkylene as defined herein.

“Alkylaminocarbonylalkoxy” means a group of the formula —O—R—C(O)—NHR′wherein R is alkylene and R′ is alkyl as defined herein.

“Dialkylaminocarbonylalkoxy” means a group of the formula—O—R—C(O)—NR′R″ wherein R is alkylene and R′ and R″ are alkyl as definedherein.

“Alkylaminoalkoxy” means a group of the formula —O—R—NHR′ wherein R isalkylene and R′ is alkyl as defined herein.

“Dialkylaminoalkoxy” means a group of the formula —O—R—NR′R′ wherein Ris alkylene and R′ and R″ are alkyl as defined herein.

“Alkylsulfonyl” means a moiety of the formula —SO₂R, wherein R is alkylas defined herein.

“Alkylsulfonylalkyl means a moiety of the formula —R′—SO₂—R″ where whereR′ is alkylene and R″ is alkyl as defined herein.

“Alkylsulfonylalkoxy” means a group of the formula —O—R—SO₂—R′ wherein Ris alkylene and R′ is alkyl as defined herein.

“Amino means a moiety of the formula —NRR′ wherein R and R′ eachindependently is hydrogen or alkyl as defined herein. “Amino thusincludes “alkylamino (where one of R and R′ is alkyl and the other ishydrogen) and “dialkylamino (where R and R′ are both alkyl.

“Aminocarbonyl” means a group of the formula —C(O)—R wherein R is aminoas defined herein.

“Alkoxyamino” means a moiety of the formula —NR—OR′ wherein R ishydrogen or alkyl and R′ is alkyl as defined herein.

“Alkylsulfanyl” means a moiety of the formula —SR wherein R is alkyl asdefined herein.

“Aminoalkyl” means a group —R—R′ wherein R′ is amino and R is alkyleneas defined herein. “Aminoalkyl” includes aminomethyl, aminoethyl,1-aminopropyl, 2-aminopropyl, and the like. The amino moiety of“aminoalkyl” may be substituted once or twice with alkyl to provide“alkylaminoalkyl” and “dialkylaminoalkyl” respectively.“Alkylaminoalkyl” includes methylaminomethyl, methylaminoethyl,methylaminopropyl, ethylaminoethyl and the like. “Dialkylaminoalkyl”includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl,N-methyl-N-ethylaminoethyl, and the like.

“Aminoalkoxy” means a group —OR—R′ wherein R′ is amino and R is alkyleneas defined herein.

“Alkylsulfonylamido” means a moiety of the formula —NR′SO₂—R wherein Ris alkyl and R′ is hydrogen or alkyl.

“Aminocarbonyloxyalkyl” or “carbamylalkyl” means a group of the formula—R—O—C(O)—NR′R″ wherein R is alkylene and R′, R″ each independently ishydrogen or alkyl as defined herein.

“Aminoalkylaminocarbonylalkyl” means a group of the formula—R—C(O)—NR′—R—NR′R″ wherein R is alkylene and each R′, R″ isindependently hydrogen or alkyl as defined herein.

“Alkynylalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is alkynyl as defined herein.

“Aryl” means a monovalent cyclic aromatic hydrocarbon moiety consistingof a mono-, bi- or tricyclic aromatic ring. The aryl group can beoptionally substituted as defined herein. Examples of aryl moietiesinclude, but are not limited to, phenyl, naphthyl, phenanthryl,fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl,methylenediphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl,diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxylyl,benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperadinyl,benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl,methylenedioxyphenyl, ethylenedioxyphenyl, and the like, includingpartially hydrogenated derivatives thereof, each being optionallysubstituted.

“Arylalkyl” and “Aralkyl”, which may be used interchangeably, mean aradical-R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is an arylgroup as defined herein; e.g., phenylalkyls such as benzyl, phenylethyl,3-(3-chlorophenyl)-2-methylpentyl, and the like are examples ofarylalkyl.

“Arylsulfonyl means a group of the formula —SO₂—R wherein R is aryl asdefined herein.

“Aryloxy” means a group of the formula —O—R wherein R is aryl as definedherein.

“Aralkyloxy” means a group of the formula —O—R—R″ wherein R is alkyleneand R′ is aryl as defined herein.

“Carboxy” or “hydroxycarbonyl”, which may be used interchangeably, meansa group of the formula —C(O)—OH.

“Cyanoalkyl” ” means a moiety of the formula —R′R″, where R′ is alkyleneas defined herein and R″ is cyano or nitrile.

“Cycloalkyl” means a monovalent saturated carbocyclic moiety consistingof mono- or bicyclic rings. Preferred cycloalkyl are unsubstituted orsubstituted with alkyl. Cycloalkyl can optionally be substituted withone or more substituents, wherein each substituent is independentlyhydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, ordialkylamino, unless otherwise specifically indicated. Examples ofcycloalkyl moieties include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like,including partially unsaturated (cycloalkenyl) derivatives thereof.

“Cycloalkylalkyl” means a moiety of the formula —R′R″, where R′ isalkylene and R″ is cycloalkyl as defined herein.

“Cycloalkylalkoxy” means a group of the formula —O—R—R′ wherein R isalkylene and R′ is cycloalkyl as defined herein.

Heteroalkyl” means an alkyl radical as defined herein wherein one, twoor three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—NR^(b)R^(c) and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom, wherein R^(a) is hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) are independentlyof each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; andwhen n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl,and when n is 1 or 2, R^(d) is alkyl, cycloalkyl, cycloalkylalkyl,amino, acylamino, monoalkylamino, or dialkylamino. Representativeexamples include, but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl,methylaminosulfonylpropyl, and the like.

“Heteroaryl” means a monocyclic or bicyclic radical of 5 to 12 ringatoms having at least one aromatic ring containing one, two, or threering heteroatoms selected from N, O, or S, the remaining ring atomsbeing C, with the understanding that the attachment point of theheteroaryl radical will be on an aromatic ring. The heteroaryl ring maybe optionally substituted as defined herein. Examples of heteroarylmoieties include, but are not limited to, optionally substitutedimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl,pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl,isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl,benzimidazolyl, benzooxazolyl, benzoxadiazolyl, benzothiazolyl,benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl,triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl,naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyland the like, including partially hydrogenated derivatives thereof, eachoptionally substituted.

Heteroarylalkyl” or “heteroaralkyl” means a group of the formula —R—R′wherein R is alkylene and R′ is heteroaryl as defined herein.

“Heteroarylsulfonyl means a group of the formula —SO₂—R wherein R isheteroaryl as defined herein.

“Heteroaryloxy” means a group of the formula —O—R wherein R isheteroaryl as defined herein.

“Heteroaralkyloxy” means a group of the formula —O—R—R″ wherein R isalkylene and R′ is heteroaryl as defined herein.

The terms “halo”, “halogen” and “halide”, which may be usedinterchangeably, refer to a substituent fluoro, chloro, bromo, or iodo.

“Haloalkyl” means alkyl as defined herein in which one or more hydrogenhas been replaced with same or different halogen. Exemplary haloalkylsinclude —CH₂Cl, —CH₂CF₃, —CH₂CCl₃, perfluoroalkyl (e.g., —CF₃), and thelike.

“Haloalkoxy” means a moiety of the formula —OR, wherein R is a haloalkylmoiety as defined herein. An exemplary haloalkoxy is difluoromethoxy.

“Heterocycloamino” means a saturated ring wherein at least one ring atomis N, NH or N-alkyl and the remaining ring atoms form an alkylene group.

“Heterocyclyl” means a monovalent saturated moiety, consisting of one tothree rings, incorporating one, two, or three or four heteroatoms(chosen from nitrogen, oxygen or sulfur). The heterocyclyl ring may beoptionally substituted as defined herein. Examples of heterocyclylmoieties include, but are not limited to, optionally substitutedpiperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl,pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl,benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl,tetrahydropyranyl, thiamorpholinyl, thiamorpholinylsulfoxide,thiamorpholinylsulfone, dihydroquinolinyl, dihydroisoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

“Heterocyclylalkyl” means a moiety of the formula —R—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Heterocyclyloxy” means a moiety of the formula —OR wherein R isheterocyclyl as defined herein.

“Heterocyclylalkoxy” means a moiety of the formula —OR—R′ wherein R isalkylene and R′ is heterocyclyl as defined herein.

“Hydroxyalkoxy” means a moiety of the formula —OR wherein R ishydroxyalkyl as defined herein.

“Hydroxyalkylamino” means a moiety of the formula —NR—R′ wherein R ishydrogen or alkyl and R′ is hydroxyalkyl as defined herein.

“Hydroxyalkylaminoalkyl” means a moiety of the formula —R—NR′—R″ whereinR is alkylene, R′ is hydrogen or alkyl, and R″ is hydroxyalkyl asdefined herein.

“Hydroxycarbonylalkyl” or “carboxyalkyl” means a group of the formula—R—(CO)—OH where R is alkylene as defined herein.

“Hydroxycarbonylalkoxy” means a group of the formula —O—R—C(O)—OHwherein R is alkylene as defined herein.

“Hydroxyalkyloxycarbonylalkyl” or “hydroxyalkoxycarbonylalkyl” means agroup of the formula —R—C(O)—O—R—OH wherein each R is alkylene and maybe the same or different.

“Hydroxyalkyl” means an alkyl moiety as defined herein, substituted withone or more, preferably one, two or three hydroxy groups, provided thatthe same carbon atom does not carry more than one hydroxy group.Representative examples include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl

“Hydroxycycloalkyl” means a cycloalkyl moiety as defined herein whereinone, two or three hydrogen atoms in the cycloalkyl radical have beenreplaced with a hydroxy substituent. Representative examples include,but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl, and the like.

“Urea” or “ureido” means a group of the formula —NR′—C(O)—NR″R′″ whereinR′, R″ and R′″ each independently is hydrogen or alkyl.

“Carbamate” means a group of the formula —O—C(O)—NR′R″ wherein R′ and R″each independently is hydrogen or alkyl.

“Carboxy” means a group of the formula —O—C(O)—OH.

“Sulfonamido” means a group of the formula —SO₂—NR′R″ wherein R′, R″ andR′″ each independently is hydrogen or alkyl.

“Triazinyl” as used herein includes [1,2,4]triazinyl, [1,2,3]triazinyland [1,4,5]triazinyl, including partially hydrogenated derivativesthereof. Triazinyl may be optionally substituted as defined herein.Preferred substituents for triazinyl include oxo, alkyl andhydroxyalkyl. Triazinyl thus encompasses, for example,3,5-dioxo-4,5-dihydro-[1,2,4]triazin-2-yl and4-methyl-3,5-dioxo-4,5-dihydro-[1,2,4]triazin-2-yl.

“Optionally substituted”, when used in association with “aryl”, phenyl”,“heteroaryl” “cycloalkyl” or “heterocyclyl”, means an aryl, phenyl,heteroaryl, cycloalkyl or heterocyclyl which is optionally substitutedindependently with one to four substituents, preferably one or twosubstituents selected from alkyl, cycloalkyl, cycloalkylalkyl,heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,acylamino, mono-alkylamino, di-alkylamino, halo alkyl, haloalkoxy,heteroalkyl, —COR, —SO₂R (where R is hydrogen, alkyl, phenyl orphenylalkyl), —(CR′R″)_(n)—COOR (where n is an integer from 0 to 5, R′and R″ are independently hydrogen or alkyl, and R is hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or—(CR′R″)_(n)—CONR^(a)R^(b) (where n is an integer from 0 to 5, R′ and R″are independently hydrogen or alkyl, and R^(a) and R^(b) are,independently of each other, hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, phenyl or phenylalkyl). Certain preferred optionalsubstituents for “aryl”, phenyl”, “heteroaryl” “cycloalkyl” or“heterocyclyl” include alkyl, halo, haloalkyl, alkoxy, cyano, amino andalkylsulfonyl. More preferred substituents are methyl, fluoro, chloro,trifluoromethyl, methoxy, amino and methanesulfonyl.

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under substitution reaction conditions. Examples ofleaving groups include, but are not limited to, halogen, alkane- orarylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy,thiomethyl, benzenesulfonyloxy, tosyloxy, and thienyloxy,dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy,acyloxy, and the like.

“Modulator” means a molecule that interacts with a target. Theinteractions include, but are not limited to, agonist, antagonist, andthe like, as defined herein.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Disease” and “Disease state” means any disease, condition, symptom,disorder or indication.

“Inert organic solvent” or “inert solvent” means the solvent is inertunder the conditions of the reaction being described in conjunctiontherewith, including for example, benzene, toluene, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, chloroform, methylene chlorideor dichloromethane, dichloroethane, diethyl ether, ethyl acetate,acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol,tert-butanol, dioxane, pyridine, and the like. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert solvents.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, as defined herein, and that possess thedesired pharmacological activity of the parent compound. Such saltsinclude:

acid addition salts formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid,benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid,ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid,glutamic acid, glycolic acid, hydroxynaphtoic acid,2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid,malonic acid, mandelic acid, methanesulfonic acid, muconic acid,2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinicacid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, andthe like; or

salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic or inorganicbase. Acceptable organic bases include diethanolamine, ethanolamine,N-methylglucamine, triethanolamine, tromethamine, and the like.Acceptable inorganic bases include aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

The preferred pharmaceutically acceptable salts are the salts formedfrom acetic acid, hydrochloric acid, sulphuric acid, methanesulfonicacid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium,potassium, calcium, zinc, and magnesium.

It should be understood that all references to pharmaceuticallyacceptable salts include solvent addition forms (solvates) or crystalforms (polymorphs) as defined herein, of the same acid addition salt.

“Protective group” or “protecting group” means the group whichselectively blocks one reactive site in a multifunctional compound suchthat a chemical reaction can be carried out selectively at anotherunprotected reactive site in the meaning conventionally associated withit in synthetic chemistry. Certain processes of this invention rely uponthe protective groups to block reactive nitrogen and/or oxygen atomspresent in the reactants. For example, the terms “amino-protectinggroup” and “nitrogen protecting group” are used interchangeably hereinand refer to those organic groups intended to protect the nitrogen atomagainst undesirable reactions during synthetic procedures. Exemplarynitrogen protecting groups include, but are not limited to,trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl(carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. Theartisan in the art will know how to chose a group for the ease ofremoval and for the ability to withstand the following reactions.

“Solvates” means solvent additions forms that contain eitherstoichiometric or non stoichiometric amounts of solvent. Some compoundshave a tendency to trap a fixed molar ratio of solvent molecules in thecrystalline solid state, thus forming a solvate. If the solvent is waterthe solvate formed is a hydrate, when the solvent is alcohol, thesolvate formed is an alcoholate. Hydrates are formed by the combinationof one or more molecules of water with one of the substances in whichthe water retains its molecular state as H₂O, such combination beingable to form one or more hydrate.

“Subject” means mammals and non-mammals. Mammals means any member of themammalia class including, but not limited to, humans; non-human primatessuch as chimpanzees and other apes and monkey species; farm animals suchas cattle, horses, sheep, goats, and swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. Examples of non-mammalsinclude, but are not limited to, birds, and the like. The term “subject”does not denote a particular age or sex.

“Arthritis” means diseases or conditions damage to joints of the bodyand pain associated with such joint damage. Arthritis includesrheumatoid arthritis, osteoarthritis, psoriatic arthritis, septicarthritis and gouty arthritis.

“Pain” includes, without limitation, inflammatory pain; surgical pain;visceral pain; dental pain; premenstrual pain; central pain; pain due toburns; migraine or cluster headaches; nerve injury; neuritis;neuralgias; poisoning; ischemic injury; interstitial cystitis; cancerpain; viral, parasitic or bacterial infection; post-traumatic injury; orpain associated with irritable bowel syndrome.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The terms “those defined above” and “those defined herein” whenreferring to a variable incorporates by reference the broad definitionof the variable as well as preferred, more preferred and most preferreddefinitions, if any.

“Treating” or “treatment” of a disease state includes:

-   -   (i) preventing the disease state, i.e. causing the clinical        symptoms of the disease state not to develop in a subject that        may be exposed to or predisposed to the disease state, but does        not yet experience or display symptoms of the disease state.    -   (ii) inhibiting the disease state, i.e., arresting the        development of the disease state or its clinical symptoms, or    -   (iii) relieving the disease state, i.e., causing temporary or        permanent regression of the disease state or its clinical        symptoms.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

Nomenclature and Structures

In general, the nomenclature used in this application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. Chemical structures shownherein were prepared using ISIS® version 2.2. Any open valency appearingon a carbon, oxygen sulfur or nitrogen atom in the structures hereinindicates the presence of a hydrogen atom unless indicated otherwise.Where a chiral center exists in a structure but no specificstereochemistry is shown for the chiral center, both enantiomersassociated with the chiral center are encompassed by the structure.Where a structure shown herein may exist in multiple tautomeric forms,all such tautomers are encompassed by the structure. The atomsrepresented in the structures herein are intended to encompass allnaturally occurring isotopes of such atoms. Thus, for example, thehydrogen atoms represented herein are meant to include also deuteriumand tritium isotopes, and the carbon atoms are meant to include C¹³ andC¹⁴ isotopes.

All patents and publications identified herein are incorporated hereinby reference in their entirety.

Compounds of the Invention

The invention provides compounds of the formula I:

or pharmaceutically acceptable salts thereof,wherein:

m is 0 or 1;

n is 0 or 1;

p is from 0 to 4;

q is 0 or 1;

R¹ is:

-   -   hydrogen;    -   C₁₋₆alkyl;    -   hydroxy-C₁₋₆alkyl;    -   C₁₋₆alkoxy-C₁₋₆alkyl;    -   hydroxy C₁₋₆alkoxy-C₁₋₆alkyl; or    -   aminocarbonyl-C₁₋₆alkyl;

R² is:

-   -   optionally substituted aryl;    -   optionally substituted heteroaryl;    -   C₃₋₆cycloalkyl; or    -   C₁₋₆alkyl; and

R³ is:

-   -   hydrogen;    -   C₁₋₆alkyl;    -   alkylcarbonylalkyl; or    -   alkoxycarbonylalkyl;

R⁴ and R⁵ each independently is:

-   -   hydrogen; or    -   C₁₋₆alkyl;

each R⁶ is independently: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl;halo-C₁₋6alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfanyl;C₁₋₆alkylsulfinyl; phenylsulfonyl wherein the phenyl portion isoptionally substituted with C₁₋₆alkyl; nitrile; hydroxy;C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkoxycarbonyl;C₁₋₆alkoxycarbonyl-C₁₋₆alkoxy; hydroxycarbonyl;hydroxycarbonyl-C₁₋₆alkoxy; C₁₋₆alkylaminocarbonyl-C₁₋₆alkoxy;C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylamino-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkoxy; amino; amino-C₁₋₆alkyl; C₁₋₆alkenyl;C₁₋₆alkynyl; morpholinyl; morpholinyl-C₁₋₆alkyl; piperazinyl;piperidinyloxy; aminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxyamino-C₁₋₆alkyl;hydroxy-C₁₋₆alkylamino-C₁₋₆alkyl; C₁₋₆alkoxycarbonylamino-C₁₋₆alkyl;C₁₋₆alkylcarbonylamino-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl;C₁₋₆alkoxycarbonylC₁₋₆alkyl; C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl;C₁₋₆alkylamino-C₁₋₆alkyl; hydroxycarbonyl-C₁₋₆alkyl; hydroxyC₁₋₆alkoxy-C₁₋₆alkyl; or nitro; or two adjacent substituents may form aC₁₋₂alkylenedioxy or halo-C₁₋₂alkylenedioxy; and

A is a five or six membered heteroaryl ring that is optionallysubstituted.

In certain embodiments of formula I, m is 0.

In certain embodiments of formula I, n is 0.

In certain embodiments of formula I, p is from 0 to 3.

In certain embodiments of formula I, p is from 0 to 2.

In certain embodiments of formula I, p is 1 or 2.

In certain embodiments of formula I, p is 1.

In certain embodiments of formula I, p is 2.

In certain embodiments of formula I, q is 0.

In certain embodiments of formula I, q is 1.

In certain embodiments of formula I, R¹ is hydrogen.

In certain embodiments of formula I, R¹ is C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is methyl.

In certain embodiments of formula I, R¹ is hydroxy-C₁₋₆alkyl.

In certain embodiments of formula I, R¹ is C₁₋₆alkoxy-C₁₋₆alkyl.

In certain embodiments of formula I, R² is optionally substituted aryl.

In certain embodiments of formula I, R² is C₁₋₆alkyl. In specificembodiments R² may be C₃₋₆ branched alkyl.

In certain embodiments of formula I, R² is optionally substitutedphenyl.

In certain embodiments of formula I, R² is phenyl optionally substitutedone, two, three or four times with a substituent or substituents eachindependently selected from: halo; C₁₋₆alkyl; C₁₋₆alkoxy;halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfanyl;C₁₋₆alkylsulfinyl; phenylsulfonyl wherein the phenyl portion isoptionally substituted with C₁₋₆alkyl; nitrile; hydroxy;C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkoxycarbonyl;C₁₋₆alkoxycarbonyl-C₁₋₆alkoxy; hydroxycarbonyl;hydroxycarbonyl-C₁₋₆alkoxy; C₁₋₆alkylaminocarbonyl-C₁₋₆alkoxy;C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylamino-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl-C₁₋₆1alkoxy; hydroxy-C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkoxy; amino; amino-C₁₋₆alkyl; C₁₋₆alkenyl;C₁₋₆alkynyl; morpholinyl; morpholinyl-C₁₋₆alkyl; piperazinyl;piperidinyloxy; aminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxyamino-C₁₋₆alkyl;hydroxy-C₁₋₆alkylamino-C₁₋₆alkyl; C₁₋₆alkoxycarbonylamino-C₁₋₆alkyl;C₁₋₆alkylcarbonylamino-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl;C₁₋₆alkoxycarbonylC₁₋₆alkyl; C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl;C₁₋₆alkylamino-C₁₋₆alkyl; hydroxycarbonyl-C₁₋₆alkyl; or nitro; or twoadjacent substituents may form a C₁₋₂alkylenedioxy orhalo-C₁₋₂alkylenedioxy.

In certain embodiments of formula I, R² is phenyl optionally substitutedonce or twice with a substituent or substituents each independentlyselected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy;ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl;methanesulfanyl; methanesulfinyl; toluenesulfonyl; nitrile; acetyl;aminocarbonyl; methoxycarbonyl; methoxycarbonylmethoxy; carboxy;hydroxycarbonylmethoxy; methylaminocarbonylmethoxy; methoxyethoxy;hydroxyethoxy; methylaminoethoxy; methanesulfonylpropyloxy;hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; amino; or nitro; or twoadjacent substituents may form methylenedioxy, ethylenedioxy ordifluoromethylenedioxy.

In certain embodiments of formula I, R² is phenyl optionally substitutedonce or twice with a substituent or substituents each independentlyselected from: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl;halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; nitrile; alkoxyalkoxy;hydroxyalkoxy; alkylsulfonylalkoxy; hydroxyalkyl; orC₃₋₆cycloalkyl-C₁₋6alkoxy.

In certain embodiments of formula I, R² is phenyl optionally substitutedonce or twice with a substituent or substituents each independentlyselected from: fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy;ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile;methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; orcyclopropylmethoxy.

In certain embodiments of formula I, R² is phenyl optionally substitutedonce or twice with a substituent or substituents each independentlyselected from: fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy;trifluoromethyl; difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy;hydroxymethyl; hydroxyethyl; or cyclopropylmethoxy.

In certain embodiments of formula I, R² is phenyl substituted once ortwice with a substituent or substituents each independently selectedfrom: halo; methyl; methoxy; trifluoromethyl; difluoromethoxy; nitrile;or methanesulfonyl.

In certain embodiments of formula I, R² is phenyl substituted once ortwice with a substituent or substituents each independently selectedfrom: fluoro; chloro; methyl; methoxy; or nitrile.

In certain embodiments of formula I, R² is phenyl substituted once ortwice with fluoro.

In certain embodiments of formula I, R² is: phenyl; 4-fluoro-phenyl;3-fluoro-phenyl; 2-fluoro-phenyl; 2-chloro-phenyl; 3,4-difluoro-phenyl;3,5-difluoro-phenyl; 3-methyl-phenyl; 4-methyl-phenyl; or3-cyano-phenyl.

In certain embodiments of formula I, R² is: phenyl; 4-fluoro-phenyl;3-fluoro-phenyl; 2-fluoro-phenyl; 2-chloro-phenyl; 3,4-difluoro-phenyl;or 3,5-difluoro-phenyl.

In certain embodiments of formula I, R² is 4-fluoro-phenyl.

In certain embodiments of formula I, R² is 3-fluoro-phenyl.

In certain embodiments of formula I, R² is 3,4-difluoro-phenyl.

In certain embodiments of formula I, R³, R⁴ and R⁵ are hydrogen.

In certain embodiments of formula I, R³, R⁴, R⁵ and R¹ are hydrogen.

In certain embodiments of formula I, R³ is hydrogen.

In certain embodiments of formula I, R⁴ is hydrogen.

In certain embodiments of formula I, R⁵ is hydrogen.

In certain embodiments of formula I, each R⁶ is independently: halo;C₁₋6alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfanyl; C₁₋₆alkylsulfinyl; phenylsulfonylwherein the phenyl portion is optionally substituted with C₁₋₆alkyl;nitrile; hydroxy; C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkoxycarbonyl;C₁₋₆alkoxycarbonyl-C₁₋₆alkoxy; hydroxycarbonyl;hydroxycarbonyl-C₁₋₆alkoxy; C₁₋₆alkylaminocarbonyl-C₁₋₆alkoxy;C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylamino-C₁₋₆alkoxy;C₁₋₆alkylsulfony-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkoxy; amino; amino-C₁₋₆alkyl; C₁₋₆alkenyl;C₁₋₆alkynyl; morpholinyl; morpholinyl-C₁₋₆alkyl; piperazinyl;piperidinyloxy; aminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxyamino-C₁₋₆alkyl;hydroxy-C₁₋₆alkylamino-C₁₋₆alkyl; C₁₋₆alkoxycarbonylamino-C₁₋₆alkyl;C₁₋6alkylcarbonylamino-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl;C₁₋₆alkoxycarbonylC₁₋₆alkyl; C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl;C₁₋₆alkylamino-C₁₋₆alkyl; hydroxycarbonyl-C₁₋₆alkyl; hydroxyC₁₋₆alkoxy-C₁₋₆alkyl; or nitro; or two adjacent substituents may form aC₁₋₂alkylenedioxy or halo-C₁₋₂alkylenedioxy.

In certain embodiments of formula I, each R⁶ is independently: fluoro;chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl;difluoromethoxy; trifluoromethoxy; methanesulfonyl; methanesulfanyl;methanesulfinyl; toluenesulfonyl; nitrile; acetyl; aminocarbonyl;methoxycarbonyl; methoxycarbonylmethoxy; carboxy;hydroxycarbonylmethoxy; methylaminocarbonylmethoxy; methoxyethoxy;hydroxyethoxy; methylaminoethoxy; methanesulfonylpropyloxy;hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; amino; or nitro;morpholinyl; N,N-dimethylaminocarbonylmethoxy; boc-piperazinyl;N-(2-methoxyethyl)-N-methylaminomethyl; N,N-dimethylaminomethyl;aminomethyl; boc-aminomethyl; methylcarbonylaminomethyl;N,N-di-(2-hydroxyethyl)-aminomethyl; morpholinylmethyl;2-hydroxy-1-hydroxymethyl-ethyl; methylaminocarbonyl; piperidinyloxy;tert-butoxycarbonylmethyl; N,N-dimethylaminocarbonylmethyl; n-propyl;isopropyl; hydroxycarbonylmethyl; hydroxypropoxy; or two adjacentsubstituents may form methylenedioxy, ethylenedioxy ordifluoromethylenedioxy.

In certain embodiments of formula I, each R⁶ is independently: halo;C₁₋6alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl; nitrile; C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkylamino;C₁₋₂alkylenedioxy; or C₃₋₆cycloalkyl-C₁₋₆alkoxy.

In certain embodiments of formula I, R¹ is phenyl substituted one, two,three or four times with a substituent or substituents eachindependently selected from: fluoro; chloro; bromo; iodo; methyl; ethyl;methoxy; ethoxy; trifluoromethyl; difluoromethoxy; methanesulfonyl;nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl;hydroxypropoxy; methylenedioxy; or ethylenedioxy.

In certain embodiments of formula I, R¹ is phenyl substituted at the twoposition with halo or C₁₋₆alkyl, and substituted one or two additionaltimes with a substituent or substituents each independently selectedfrom: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl; nitrile; C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkylamino;C₁₋₂alkylenedioxy; or C₃₋₆cycloalkyl-C₁₋₆alkoxy.

In certain embodiments of formula I, each R⁶ is independently: halo;C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl; nitrile; C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl; hydroxy-C₁₋₆alkylamino;C₁₋₂alkylenedioxy; or C₃₋₆cycloalkyl-C₁₋₆alkoxy.

In certain embodiments of formula I, R¹ is phenyl substituted two orthree times with substituents each independently selected from: fluoro;chloro; bromo; methyl; ethyl; methoxy; ethoxy; difluoromethoxy;methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl;hydroxypropoxy; methylenedioxy; or ethylenedioxy.

In certain embodiments of formula I, R¹ is phenyl substituted two orthree times with substituents each independently selected from: fluoro;chloro; bromo; methyl; and methoxy.

In certain embodiments of formula I, each R⁶ is independently: fluoro;chloro; bromo; methyl; ethyl; methoxy; ethoxy; trifluoromethyl;difluoromethoxy; nitrile; methoxyethoxy; hydroxyethoxy; hydroxymethyl;hydroxyethyl; or cyclopropylmethoxy.

In certain embodiments of formula I, each R⁶ is independently: hydrogen;halo; ethyl; or methyl.

In certain embodiments of formula I, each R⁶ is independently: halo; orC₁₋₆alkyl.

In certain embodiments of formula I, each R⁶ is independently: chloro;or methyl.

In certain embodiments of formula I, p is 1 and R⁶ is halo or C₁₋₆alkyl.

In certain embodiments of formula I, p is 1 and R⁶ is chloro or methyl.

In certain embodiments of formula I, p is 1 and R⁶ is halo.

In certain embodiments of formula I, p is 1 and R⁶ is C₁₋₆alkyl.

In certain embodiments of formula I, p is 1 and R⁶ is chloro.

In certain embodiments of formula I, p is 1 and R⁶ is methyl.

In certain embodiments of formula I, p is 1 and R⁶ is ethyl.

In certain embodiments of formula I, p is 2, one of R⁶ is C₁₋₆alkyl, andthe other is chloro.

In certain embodiments of formula I, p is 2, one of R⁶ is methyl, andthe other is halo.

In certain embodiments of formula I, p is 2, one of R⁶ is ethyl, and theother is halo.

In certain embodiments of formula I, p is 1 and R⁶ is halo or C₁₋₆alkylat the 2-position.

In certain embodiments of formula I, p is 1 and R⁶ is chloro or methylat the 2-position.

In certain embodiments of formula I, p is 1 and R⁶ is halo at the2-position.

In certain embodiments of formula I, p is 1 and R⁶ is C₁₋₆alkyl at the2-position.

In certain embodiments of formula I, p is 1 and R⁶ is chloro at the2-position.

In certain embodiments of formula I, p is 1 and R⁶ is methyl at the2-position.

In certain embodiments of formula I, A is a five- or six-memberedheteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl;isoxazolyl; thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl;oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; ortriazinyl, each optionally substituted.

In certain embodiments of formula I, A is a five- or six-memberedheteroaryl selected from: pyrrolyl; pyrazolyl; imidazolyl, pyrrolidinyl,triazolyl; tetrazolyl; oxazolyl; isoxazolyl; thiazolyl; isothiazolyl;thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl; morpholinyl,pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, each optionallysubstituted.

In certain embodiments of formula I, A is a five-membered heteroarylselected from: pyrrolyl; pyrazolyl; triazolyl; oxazolyl; isoxazolyl;thiazolyl; isothiazolyl; thiadiazolyl; oxadiazolyl; or oxazolidinyl,each optionally substituted.

In certain embodiments of formula I, A is a five- or six-memberedheteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; isoxazolyl;oxadiazolyl; oxazolidinyl; pyridinyl; or triazinyl, each optionallysubstituted.

In certain embodiments of formula I, A is a six-membered heteroarylselected from: pyridinyl; pyrimidinyl; pyrazinyl; pyridazinyl; ortriazinyl, each optionally substituted.

In certain embodiments of formula I, A is a five- or six-memberedheteroaryl selected from: pyrrolyl; pyrazolyl; triazolyl; isoxazolyl;oxadiazolyl; oxazolidinyl; pyridinyl; pyrimidinyl; pyrazinyl;pyridazinyl; or triazinyl, each optionally substituted.

In certain embodiments of formula I, A is a five-membered heteroarylselected from: pyrrolyl; pyrazolyl; triazolyl; isoxazolyl; oxadiazolyl;or oxazolidinyl, each optionally substituted.

In certain embodiments of formula I, A is a six-membered heteroarylselected from: pyridinyl; triazinyl, pyrimidinyl; pyrazinyl; orpyridazinyl; each optionally substituted

In certain embodiments of formula I, A is a six-membered heteroarylselected from: pyridinyl or triazinyl each optionally substituted.

In certain embodiments of formula I, A is optionally substitutedpyrazolyl.

In certain embodiments of formula I, A is optionally substituted[1,2,4]triazin-2-yl.

In certain embodiments of formula I, A is optionally substitutedpyrimidinyl.

In certain embodiments of formula I, A is optionally substitutedpyrazinyl.

In certain embodiments of formula I, A is optionally substitutedpyridazinyl.

In certain embodiments of formula I, A is optionally substitutedpyridinyl.

In certain embodiments of formula I, A is optionally substitutedthiazolyl.

In certain embodiments of formula I, A is [1,2,4]triazin-2-yl optionallysubstituted once or twice with oxo and once with alkyl or hydroxyalkyl.

In certain embodiments of formula I, A is3,5-dioxo-4,5-dihydro-[1,2,4]triazin-2-yl optionally substituted withC₁₋₆alkyl.

In certain embodiments of formula I, A is pyrazolyl optionallysubstituted once or twice with C₁₋₆alkyl; hydroxy C₁₋₆alkoxy-C₁₋₆alkyl;or hydroxy-C₁₋₆alkyl.

In certain embodiments of formula I, A is optionally substituted one,two or three times with a group or groups each independently selectedfrom: C₁₋₆₋alkyl; C₁₋₆₋alkoxy; hydroxy-C₁₋₆₋alkyl;C₁₋₆₋alkoxy-C₁₋₆₋alkyl; halo; halo-C₁₋₆₋alkyl;C₁₋₆₋alkylsulfonyl-C₁₋₆₋alkyl; C₁₋₆₋alkylsulfanyl-C₁₋₆₋alkyl; hydroxyC₁₋₆alkoxy-C₁₋₆alkyl; C₁₋6alkoxycarbonyl-C₁₋₆alkyl; C₃₋₆cycloalkyl;hydroxycarbonyl-C₁₋₆alkyl; amino-C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl; oroxo.

In certain embodiments of formula I, A is optionally substituted one,two or three times with a group or groups each independently selectedfrom: C₁₋₆₋alkyl; hydroxy-C₁₋₆₋alkyl; C₁₋₆₋alkoxy-C₁₋₆₋alkyl; halo;halo-C₁₋₆₋alkyl; C₁₋₆₋alkylsulfonyl-C₁₋₆₋alkyl;C₁₋₆₋alkylsulfanyl-C₁₋₆₋alkyl; hydroxy C₁₋₆alkoxy-C₁₋₆alkyl; or oxo.

In certain embodiments of formula I, A is optionally substituted one,two or three times with a group or groups each independently selectedfrom: C₁₋₆₋alkyl; hydroxy-C₁₋₆₋alkyl; hydroxy C₁₋₆alkoxy-C₁₋₆alkyl; oroxo.

In certain embodiments of formula I, A is optionally substituted one ortwo times with a group or groups each independently selected from:C₁₋₆₋alkyl; hydroxy-C₁₋₆₋alkyl; C₁₋₆₋alkoxy-C₁₋₆₋alkyl; halo;halo-C₁₋₆₋alkyl; hydroxy C₁₋₆alkoxy-C₁₋₆alkyl; or oxo.

In certain embodiments of formula I, A is optionally substituted one ortwo times with a group or groups each independently selected from:methyl; ethyl; propyl; 2-hydroxyethyl; 2-hydroxy-propyl; isobutyl; oxo;or 2,3-dihydroxy-propyl.

In certain embodiments of formula I, A is optionally substituted one ortwo times with a group or groups each independently selected from:methyl; ethyl; propyl; 2-hydroxyethyl; 2-hydroxy-propyl; isobutyl; oxo;2,3-dihydroxy-propyl; ethoxycarbonylmethyl; 2-hydroxy-3-methoxy-propyl;carboxymethyl; methoxy; 2-(dimethylamino)-ethyl-aminocarbonylmethyl; or2-acetoxy-3-methoxy-propyl.

In certain embodiments of formula I, A is optionally substituted one ortwo times with a group or groups each independently selected from:methyl; ethyl; propyl; 2-hydroxyethyl; 2-hydroxy-propyl; oxo;2,3-dihydroxy-propyl; or 2-hydroxy-3-methoxy-propyl.

In certain embodiments of formula I, A is substituted one or two timeswith a group or groups each independently selected from: methyl; ethyl;propyl; 2-hydroxyethyl; 2-hydroxy-propyl; isobutyl; oxo; or2,3-dihydroxy-propyl.

In certain embodiments of formula I, A is substituted with methyl, andis optionally substituted with one additional group selected from:methyl; ethyl; propyl; 2-hydroxyethyl; 2-hydroxy-propyl; isobutyl; oxo;or 2,3-dihydroxy-propyl.

In certain embodiments of formula I, A is a six-membered heteroarylselected from: pyridinyl; triazinyl, pyrimidinyl; pyrazinyl; orpyridazinyl; each optionally substituted once or twice with methyl;ethyl; propyl; 2-hydroxyethyl; 2-hydroxy-propyl; oxo;2,3-dihydroxy-propyl; or 2-hydroxy-3-methoxy-propyl.

In certain embodiments of formula I, A is pyrazolyl optionallysubstituted once or twice with methyl; ethyl; propyl; 2-hydroxyethyl;2-hydroxy-propyl; 2,3-dihydroxy-propyl; or 2-hydroxy-3-methoxy-propyl.

In certain embodiments of formula I, A is a five-membered heteroarylselected from: pyrrolyl; pyrazolyl; triazolyl; isoxazolyl; oxadiazolyl;or oxazolidinyl, each optionally substituted once or twice with methyl;ethyl; propyl; 2-hydroxyethyl; 2-hydroxy-propyl; 2,3-dihydroxy-propyl;or 2-hydroxy-3-methoxy-propyl.

In certain embodiments of formula I, A is: pyrrol-1-yl;1-(2-hydroxy-ethyl)5-methyl-1H-pyrazol-3-yl; 2-methyl-2H-tetrazol-5-yl;1,5-dimethyl-1H-pyrazol-3-yl; 1H-pyrazol-3-yl; 5-methyl-pyridin-2-yl;1-(2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl;2-isobutyl-2H-pyrazol-3-yl; 1-methyl-1H-tetrazol-5-yl;6-methyl-pyridin-3-yl; pyrazol-1-yl;2-(2-hydroxy-ethyl)-5-methyl-2H-pyrazol-3-yl; 2-methyl-2H-pyrazol-3-yl;5-ethyl-2H-pyrazol-3-yl; 4,5-dimethyl-2H-pyrazol-3-yl;3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; 5-ethyl-1H-pyrazol-3-yl1-((R)-2,3-dihydroxy-propyl)-5-methyl-1H-pyrazol-3-yl;2,5-dimethyl-2H-pyrazol-3-yl; 5-methyl-1H-pyrazol-3-yl;5-methyl-1H-[1,2,4]triazol-3-yl; 1,5-dimethyl-1H-[1,2,4]triazol-3-yl; 3methyl-isoxazol-5-yl; 3-methyl-[1,2,4]triazol-1-yl;4-methyl-[1,2,3]triazol-1-yl; 4-methyl-pyrazol-1-yl;5-methyl-[1,3,4]oxadiazol-2-yl; 2-propyl-2H-pyrazol-3-yl;4,5-dimethyl-4H-[1,2,4]triazol-3-yl; 2-oxo-oxazolidin-3-ylmethyl;4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;5-methyl-isoxazol-3-yl; 1-(2-methoxy-ethyl)-5-methyl-1H-pyrazol-3-yl;pyrazin-2-yl; 6-methyl-pyridazin-3-yl; 5-methyl-pyrazin-2-yl;pyrrolidin-1-yl; morpholin-4-yl;4-(2-methoxy-ethyl)-5-methyl-4H-[1,2,4]triazol-3-yl;4-methyl-imidazol-1-yl;1-(ethoxycarbonylmethyl)-5-methyl-1H-pyrazol-3-yl; pyrimidin-2-yl;pyrimidin-5-yl; 2-methyl-pyrimidin-4-yl;5-chloro-3-oxo-2,3-dihydro-pyridazin-4-yl;3-oxo-2,3-dihydro-pyridazin-4-yl; thiazol-4-yl; 2-methyl-thiazol-4-yl;pyridin-4-yl; 4-ethyl-5-methyl-4H-[1,2,4]triazol-3-yl;1-(S)-2,3-dihydroxy-propyl)-5-methyl-1H-pyrazol-3-yl;5-cyclopropyl-1H-pyrazol-3-yl; 1-methyl-1H-pyrazol-3-yl;[1,2,4]triazol-4-yl; 1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl;2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl;3-oxo-2,3-dihydro-pyridazin-4-yl;1-((R)-2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl;1-(S)-2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl;1-(R)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl;1-(S)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl;4-(R)-2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;3-methyl-6-oxo-6H-pyridazin-1-yl; 6-methyl-pyrazin-2-yl;4-methyl-pyrimidin-2-yl; 6-oxo-1,6-dihydro-pyrazin-2-yl;5-methyl-1-(hydroxycarbonylmethyl)-1H-pyrazol-3-yl;1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl; 6-oxo-6H-pyridazin-1-yl;2-(2-hydroxy-ethyl)-3-oxo-2,3-dihydro-pyridazin-4-yl;1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl;6-oxo-1,6-dihydro-pyridazin-3-yl; 5-trifluoromethyl-1H-pyrazol-3-yl;2-(R)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl;2-(S)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl;1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-pyrazol-3-yl;2-oxo-1,2-dihydro-pyridin-3-yl; 6-methoxy-pyridazin-3-yl;1-[(2-dimethylamino-ethylcarbamoyl)-methyl]-5-methyl-1H-pyrazol-3-yl;1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl;1-(2-hydroxy-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl;5-methyl-2-oxo-2H-pyridin-1-yl; 3-oxo-2,3-dihydro-pyridazin-4-yl;2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl;1-((R)-2-hydroxy-3-methoxy-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl;1-(S)-2-hydroxy-3-methoxy-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl;5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl;4-ethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl;4-methyl-6-oxo-6H-pyridazin-1-yl;1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl;1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl;1-(R)-2-hydroxy-3-methoxy-propyl)-2-oxo-1,2-dihydro-pyridin-3-yl; or1-(2-acetoxy-3-methoxy)-propyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl.

In certain embodiments of formula I, A is:1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl;3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; 5-methyl-1H-pyrazol-3-yl;4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;3-oxo-2,3-dihydro-pyridazin-4-yl;2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl;3-oxo-2,3-dihydro-pyridazin-4-yl;1-(R)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl;1-(S)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl;4-(R)-2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl;2-(2-hydroxy-ethyl)-3-oxo-2,3-dihydro-pyridazin-4-yl;2-(R)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl;2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl; or4-ethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl.

In certain embodiments of formula I, A is pyrrol-1-yl.

In certain embodiments of formula I, A is1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is 2-methyl-2H-tetrazol-5-yl;

In certain embodiments of formula I, A is 1,5-dimethyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is 1H-pyrazol-3-yl.

In certain embodiments of formula I, A is 5-methyl-pyridin-2-yl.

In certain embodiments of formula I, A is1-(2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is 2-isobutyl-2H-pyrazol-3-yl.

In certain embodiments of formula I, A is 1-methyl-1H-tetrazol-5-yl.

In certain embodiments of formula I, A is 6-methyl-pyridin-3-yl.

In certain embodiments of formula I, A is pyrazol-1-yl.

In certain embodiments of formula I, A is2-(2-hydroxy-ethyl)-5-methyl-2H-pyrazol-3-yl.

In certain embodiments of formula I, A is 2-methyl-2H-pyrazol-3-yl.

In certain embodiments of formula I, A is 5-ethyl-2H-pyrazol-3-yl.

In certain embodiments of formula I, A is 4,5-dimethyl-2H-pyrazol-3-yl.

In certain embodiments of formula I, A is3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl.

In certain embodiments of formula I, A is 5-ethyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is1-(R)-2,3-dihydroxy-propyl)-5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is 2,5-dimethyl-2H-pyrazol-3-yl.

In certain embodiments of formula I, A is 5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is5-methyl-1H-[1,2,4]triazol-3-yl.

In certain embodiments of formula I, A is1,5-dimethyl-1H-[1,2,4]triazol-3-yl.

In certain embodiments of formula I, A is 3-methyl-isoxazol-5-yl.

In certain embodiments of formula I, A is 3-methyl-[1,2,4]triazol-1-yl.

In certain embodiments of formula I, A is 4-methyl-[1,2,3]triazol-1-yl.

In certain embodiments of formula I, A is 4-methyl-pyrazol-1-yl.

In certain embodiments of formula I, A is5-methyl-[1,3,4]oxadiazol-2-yl.

In certain embodiments of formula I, A is 2-propyl-2H-pyrazol-3-yl.

In certain embodiments of formula I, A is4,5-dimethyl-4H-[1,2,4]triazol-3-yl.

In certain embodiments of formula I, A is 2-oxo-oxazolidin-3-ylmethyl.

In certain embodiments of formula I, A is4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl.

In certain embodiments of formula I, A is4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl.

In certain embodiments of formula I, A is 5-methyl-isoxazol-3-yl;

In certain embodiments of formula I, A is1-(2-methoxy-ethyl)-5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is pyrazin-2-yl.

In certain embodiments of formula I, A is 6-methyl-pyridazin-3-yl.

In certain embodiments of formula I, A is 5-methyl-pyrazin-2-yl.

In certain embodiments of formula I, A is pyrrolidin-1-yl.

In certain embodiments of formula I, A is morpholin-4-yl.

In certain embodiments of formula I, A is4-(2-methoxy-ethyl)-5-methyl-4H-[1,2,4]triazol-3-yl.

In certain embodiments of formula I, A is 4-methyl-imidazol-1-yl.

In certain embodiments of formula I, A is1-(ethoxycarbonylmethyl)-5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is pyrimidin-2-yl.

In certain embodiments of formula I, A is pyrimidin-5-yl.

In certain embodiments of formula I, A is 2-methyl-pyrimidin-4-yl.

In certain embodiments of formula I, A is5-chloro-3-oxo-2,3-dihydro-pyridazin-4-yl.

In certain embodiments of formula I, A is3-oxo-2,3-dihydro-pyridazin-4-yl.

In certain embodiments of formula I, A is thiazol-4-yl.

In certain embodiments of formula I, A is 2-methyl-thiazol-4-yl.

In certain embodiments of formula I, A is pyridin-4-yl

In certain embodiments of formula I, A is4-ethyl-5-methyl-4H-[1,2,4]triazol-3-yl.

In certain embodiments of formula I, A is1-(S)-2,3-dihydroxy-propyl)-5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is 5-cyclopropyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is 1-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is [1,2,4]triazol-4-yl.

In certain embodiments of formula I, A is1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl.

In certain embodiments of formula I, A is3-oxo-2,3-dihydro-pyridazin-4-yl.

In certain embodiments of formula I, A is1-((R)-2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is1-((S)-2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is1-((R)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is1-((S)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is4-((R)-2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl.

In certain embodiments of formula I, A is3-methyl-6-oxo-6H-pyridazin-1-yl.

In certain embodiments of formula I, A is 6-methyl-pyrazin-2-yl.

In certain embodiments of formula I, A is 4-methyl-pyrimidin-2-yl.

In certain embodiments of formula I, A is6-oxo-1,6-dihydro-pyrazin-2-yl.

In certain embodiments of formula I, A is5-methyl-1-(hydroxycarbonylmethyl)-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is 6-oxo-6H-pyridazin-1-yl.

In certain embodiments of formula I, A is2-(2-hydroxy-ethyl)-3-oxo-2,3-dihydro-pyridazin-4-yl.

In certain embodiments of formula I, A is1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl.

In certain embodiments of formula I, A is6-oxo-1,6-dihydro-pyridazin-3-yl.

In certain embodiments of formula I, A is5-trifluoromethyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is2-(R)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl.

In certain embodiments of formula I, A is2-(S)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl.

In certain embodiments of formula I, A is1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is2-oxo-1,2-dihydro-pyridin-3-yl.

In certain embodiments of formula I, A is 6-methoxy-pyridazin-3-yl.

In certain embodiments of formula I, A is1-[(2-dimethylamino-ethylcarbamoyl)-methyl]-5-methyl-1H-pyrazol-3-yl.

In certain embodiments of formula I, A is1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl.

In certain embodiments of formula I, A is1-(2-hydroxy-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl.

In certain embodiments of formula I, A is5-methyl-2-oxo-2H-pyridin-1-yl.

In certain embodiments of formula I, A is3-oxo-2,3-dihydro-pyridazin-4-yl.

In certain embodiments of formula I, A is2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl.

In certain embodiments of formula I, A is1-(R)-2-hydroxy-3-methoxy-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl.

In certain embodiments of formula I, A is1-(S)-2-hydroxy-3-methoxy-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl.

In certain embodiments of formula I, A is5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl.

In certain embodiments of formula I, A is4-ethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl.

In certain embodiments of formula I, A is3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl.

In certain embodiments of formula I, A is4-methyl-6-oxo-6H-pyridazin-1-yl.

In certain embodiments of formula I, A is1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl.

In certain embodiments of formula I, A is1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl.

In certain embodiments of formula I, A is1-(R)-2-hydroxy-3-methoxy-propyl)-2-oxo-1,2-dihydro-pyridin-3-yl.

In certain embodiments of formula I, A is1-(2-acetoxy-3-methoxy)-propyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl.

In certain embodiments of formula I, A is: pyrrol-1-yl;2-hydroxy-5-methyl-pyrazol-3-yl; 2-methyl-tetrazol-5-yl;1,5-dimethyl-pyrazol-3-yl; pyrazol-3-yl; 5-methyl-pyridin-2-yl;1-(2-hydroxy-propyl)-5-methyl-pyrazol-3-yl; 2-isobutyl-pyrazol-3-yl;1-methyl-tetrazol-5-yl; 6-methyl-pyridin-3-yl; pyrazol-1-yl;2-methyl-pyrazol-3-yl; 5-ethyl-pyrazol-3-yl; 4,5-dimethyl-pyrazol-3-yl;3,5-dioxo-4-5-dihydro[1,2,4]triazin-2-yl; 5-ethyl-1H-pyrazol-3-yl;1,5-dimethyl-1H-pyrazol-3-yl;1-(R)-2,3-dihydroxy-propyl)-5-methyl-1H-pyrazol-3-yl;2,5-dimethyl-2H-pyrazol-3-yl; 5-methyl-1H-[1,2,4]triazol-3-yl;1,5-dimethyl-1H-[1,2,4]triazol-3-yl; 3-methyl-isoxazol-5-yl;3-methyl-[1,2,4]triazol-1-yl; 4-methyl-[1,2,3]triazol-1-yl;4-methyl-pyrazol-1-yl; 5-methyl-[1,3,4]oxadiazol-2-yl;2-propyl-pyrazol-3-yl; 4,5-dimethyl-[1,2,4]triazol-3-yl;2-oxo-oxazolidin-3-ylmethyl;4-methyl-3,5-dioxo-4,5-dihydro-[1,2,4]triazin-2-yl;5-methyl-pyrazol-3-yl;4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-[1,2,4]triazin-2-yl; and5-methyl-isoxazol-3-yl.

In certain embodiments, the compounds of formula I may be morespecifically of formula II:

wherein:

r is from 0 to 3;

R⁶ is: hydrogen; C₁₋₆alkyl; or halo;

R⁷ is: hydrogen; halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl;halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfanyl;C₁₋₆alkylsulfinyl; phenylsulfonyl wherein the phenyl portion isoptionally substituted with C₁₋₆alkyl; nitrile; hydroxy;C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkoxycarbonyl;C₁₋₆alkoxycarbonyl-C₁₋₆alkoxy; hydroxycarbonyl;hydroxycarbonyl-C₁₋₆alkoxy; C₁₋₆alkylaminocarbonyl-C₁₋₆alkoxy;C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylamino-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkoxy; amino; amino-C₁₋₆alkyl; C₁₋₆alkenyl;C₁₋₆alkynyl; morpholinyl; morpholinyl-C₁₋₆alkyl; piperazinyl;piperidinyloxy; aminocarbonyl-C₁₋6alkoxy; C₁₋₆alkoxyamino-C₁₋₆alkyl;hydroxy-C₁₋₆alkylamino-C₁₋₆alkyl; C₁₋₆alkoxycarbonylamino-C₁₋₆alkyl;C₁₋₆alkylcarbonylamino-C₁₋₆alkyl; C₁₋6alkylaminocarbonyl;C₁₋₆alkoxycarbonylC₁₋₆alkyl; C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl;C₁₋6alkylamino-C₁₋₆alkyl; hydroxycarbonyl-C₁₋₆alkyl; hydroxyC₁₋₆alkoxy-C₁₋₆alkyl; or nitro;

each R¹¹ independently is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl;halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; or nitrile; and

A and R′ are as defined herein.

In certain embodiments of formula II, the subject compounds may be morespecifically of formula IIa or formula IIb;

wherein p, R¹, R⁶, R⁷, and R¹¹ are as defined herein.

In certain embodiments the subject compounds are of formula IIa.

In certain embodiments the subject compounds are of formula IIb.

In certain embodiments of any of formulas II, IIa and IIb, R⁶ is halo orC₁₋₆alkyl.

In certain embodiments of any of formulas II, IIa and IIb, R⁶ isC₁₋₆alkyl.

In certain embodiments of any of formulas II, IIa and 11b, R⁶ is chloroor methyl.

In certain embodiments of any of formulas II, IIa and 11b, R⁶ is methyl.

In certain embodiments of any of formulas II, IIa and 11b, R⁶ is ethyl.

In certain embodiments of any of formulas II, IIa and 11b, R⁷ is:hydrogen; fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy;trifluoromethyl; difluoromethoxy; trifluoromethoxy; methanesulfonyl;methanesulfanyl; methanesulfinyl; toluenesulfonyl; nitrile; acetyl;aminocarbonyl; methoxycarbonyl; methoxycarbonylmethoxy; carboxy;hydroxycarbonylmethoxy; methylaminocarbonylmethoxy; methoxyethoxy;hydroxyethoxy; methylaminoethoxy; methanesulfonylpropyloxy;hydroxymethyl; hydroxyethyl; cyclopropylmethoxy; amino; or nitro;morpholinyl; N,N-dimethylaminocarbonylmethoxy; boc-piperazinyl;N-(2-methoxyethyl)-N-methylaminomethyl; N,N-dimethylaminomethyl;aminomethyl; boc-aminomethyl; methylcarbonylaminomethyl;N,N-di-(2-hydroxyethyl)-aminomethyl; morpholinylmethyl;2-hydroxy-1-hydroxymethyl-ethyl; methylaminocarbonyl; piperidinyloxy;tert-butoxycarbonylmethyl; N,N-dimethylaminocarbonylmethyl; n-propyl;isopropyl; hydroxycarbonylmethyl; or hydroxypropoxy.

In certain embodiments of any of formulas II, IIa and IIb, R⁷ is:hydrogen; fluoro; chloro; bromo; iodo; methyl; ethyl; methoxy; ethoxy;trifluoromethyl; difluoromethoxy; methanesulfonyl; nitrile;methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; orhydroxypropoxy.

In certain embodiments of any of formulas II, IIa and IIb, R⁷ is:hydrogen; fluoro; chloro; bromo; methyl; ethyl; methoxy; ethoxy;difluoromethoxy; methoxyethoxy; hydroxyethoxy; hydroxymethyl;hydroxyethyl; hydroxypropoxy; methylenedioxy; or ethylenedioxy.

In certain embodiments of any of formulas II, IIa and IIb, R⁷ is:hydrogen; fluoro; chloro; bromo; methyl; and methoxy.

In certain embodiments of any of formulas II, IIa and IIb, R⁷ is:hydrogen; or halo.

In certain embodiments of any of formulas II, IIa and IIb, R⁷ is:hydrogen; or chloro.

In certain embodiments of any of formulas II, IIa and 11b, R⁷ ishydrogen.

In certain embodiments of any of formulas II, IIa and IIb, r is 0, 1 or2.

In certain embodiments of any of formulas II, IIa and IIb, r is 1 or 2.

In certain embodiments of any of formulas II, IIa and IIb, r is 1.

In certain embodiments of any of formulas II, IIa and IIb, each R¹¹independently is: halo; C₁₋₆alkyl; or C₁₋₆alkoxy.

In certain embodiments of any of formulas II, IIa and IIb, each R¹¹independently is fluoro or methyl.

In certain embodiments of any of formulas II, IIa and IIb, R¹¹ is halo.

In certain embodiments of any of formulas II, IIa and IIb, R¹¹ isfluoro.

In certain embodiments of any of formulas II, IIa and IIb r is 1 and R¹¹is halo.

In certain embodiments of any of formulas II, IIa and IIb r is 1 and R¹¹is 3-halo or 4-halo.

In certain embodiments of any of formulas II, IIa and IIb r is 1 and R¹¹is fluoro.

In certain embodiments of any of formulas II, IIa and IIb r is 1 and R¹¹is 3-fluoro or 4-fluoro.

In certain embodiments of any of formulas II, IIa and IIb r is 1 and R¹¹is 4-fluoro.

In certain embodiments of any of formula II, IIa and IIb, R^(a) ishydrogen.

The invention also provides methods for treating a disease or conditionmediated by or otherwise associated with a P2X₇ receptor, the methodcomprising administering to a subject in need thereof an effectiveamount of a compound of the invention.

The invention also provides methods for treating an inflammatory,respiratory or diabetes condition, the method comprising administeringto a subject in need thereof an effective amount of a compound of theinvention together with an effective amount of a P2X3 inhibitor.

The disease may be an inflammatory disease such as arthritis, and moreparticularly rheumatoid arthritis, osteoarthritis, psoriasis, allergicdermatitis, asthma, chronic obstructive pulmonary disease, airwayshyper-responsiveness, septic shock, glomerulonephritis, irritable boweldisease, and Crohn's disease.

The disease may be a pain condition, such as inflammatory pain; surgicalpain; visceral pain; dental pain; premenstrual pain; central pain; paindue to burns; migraine or cluster headaches; nerve injury; neuritis;neuralgias; poisoning; ischemic injury; interstitial cystitis; cancerpain; viral, parasitic or bacterial infection; post-traumatic injury; orpain associated with irritable bowel syndrome.

The disease may be a respiratory disorder, such as chronic obstructivepulmonary disorder (COPD), asthma, or bronchospasm, or agastrointestinal (GI) disorder such as Irritable Bowel Syndrome (IBS),Inflammatory Bowel Disease (IBD), biliary colic and other biliarydisorders, renal colic, diarrhea-dominant IBS, pain associated with GIdistension.

The disease may be diabetes.

Representative compounds in accordance with the methods of the inventionare shown in Table 1, together with pIC₅₀ values for P2X7.

TABLE 1 # Structure Name pKi 1

4-(3-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylic acid(2-methyl-5-pyrrol-1-yl-phenyl)-amide 6.985 2

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-phenyl}-amide 7.735 3

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(2-methyl-2H-tetrazol-5- yl)-phenyl]-amide 6.21 4

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(1,5-dimethyl-1H-pyrazol-3-yl)-2- methyl-phenyl]-amide 7.715 5

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(1H-pyrazol-3-yl)-phenyl]- amide 7.745 6

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(5-methyl-pyridin-2-yl)- phenyl]-amide 7.07 7

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[1-(2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-phenyl}-amide 7.643 8

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(2-isobutyl-2H-pyrazol-3-yl)-2- methyl-phenyl]-amide 6.367 9

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(1-methyl-1H-tetrazol-5- yl)-phenyl]-amide 6.176 10

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(6-methyl-pyridin-3-yl)- phenyl]-amide 6.653 11

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid (2-methyl-5-pyrazol-1-yl-phenyl)-amide 7.763 12

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboyxlicacid {5-[2-(2-hydroxy-ethyl)-5-methyl-2H-pyrazol-3-yl]-2-methyl-phenyl}-amide 13

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(2-methyl-2H-pyrazol-3- yl)-phenyl]-amide 7.033 14

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(5-ethyl-2H-pyrazol-3-yl)-2-methyl- phenyl]-amide 6.913 15

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(4,5-dimethyl-2H-pyrazol-3-yl)-2- methyl-phenyl]-amide 7.79 16

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-phenyl]- amide 7.23 17

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [3-(5-ethyl-1H-pyrazol-3-yl)-phenyl]- amide 6.073 18

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [3-(1,5-dimethyl-1H-pyrazol-3-yl)- phenyl]-amide 5.72 19

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[1-((R)-2,3-dihydroxy-propyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl- phenyl}-amide 7.423 20

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [3-(2,5-dimethyl-2H-pyrazol-3-yl)- phenyl]-amide 5.31 21

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(2,5-dimethyl-2H-pyrazol-3-yl)-2- methyl-phenyl]-amide 6.525 22

(S)-4-(3-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(5-methyl-1H-pyrazol-3- yl)-phenyl]-amide 7.75 23

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(5-methyl-1H- [1,2,4]triazol-3-yl)-phenyl]-amide 24

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(1,5-dimethyl-1H-[1,2,4]triazol-3-yl)- 2-methyl-phenyl]-amide 25

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-chloro-4-(1,5-dimethyl-1H-pyrazol-3- yl)-phenyl]-amide 26

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(3-methyl-isoxazol-5-yl)- phenyl]-amide 7.265 27

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(3-methyl-[1,2,4]triazol-1- yl)-phenyl]-amide 6.28 28

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(4-methyl-[1,2,3]triazol-1- yl)-phenyl]-amide 7.145 29

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(4-methyl-pyrazol-1-yl)- phenyl]-amide 7.99 30

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(5-methyl-[1,3,4]oxadiazol- 2-yl)-phenyl]-amide 6.27531

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(5-methyl- 1H-pyrazol-3-yl)-phenyl]-amide7.35 32

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(2-propyl-2H-pyrazol-3-yl)- phenyl]-amide 6.885 33

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-chloro-5-(5-methyl-1H-pyrazol-3-yl)- phenyl]-amide 7.4067 34

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(4,5-dimethyl-4H-[1,2,4]triazol-3-yl)- 2-methyl-phenyl]-amide7.78 35

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [4-chloro-2-methyl-5-(2-oxo-oxazolidin- 3-ylmethyl)-phenyl]-amide8.135 36

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [4-chloro-3-(5-methyl-1H-pyrazol-3-yl)- phenyl]-amide 5.92 37

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenyl]-amide 7.76 38

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl- phenyl}-amide 7.46 39

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-2- methyl-phenyl}-amide 7.76 40

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(5-methyl-isoxazol-3-yl)- phenyl]-amide 7.183 41

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [4-fluoro-2-methyl-5-(5-methyl-1H- pyrazol-3-yl)-phenyl]-amide8.048 42

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[1-(2-methoxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-phenyl}-amide 7.3 43

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboyxlicacid (2-methyl-5-pyrazin-2-yl-phenyl)-amide 7.54 44

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(6-methyl-pyridazin-3-yl)- phenyl]-amide 7.567 45

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(5-methyl-pyrazin-2-yl)- phenyl]-amide 7.01 46

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid (2-methyl-5-pyrrolidin-1-yl-phenyl)- amide 7.873 47

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid (2-methyl-5-morpholin-4-yl-phenyl)- amide 6.3 48

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[4-(2-methoxy-ethyl)-5-methyl-4H-[1,2,4]triazol-3-yl]-2-methyl-phenyl}- amide 5.86 49

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(4-methyl-imidazol-1-yl)- phenyl]-amide 6.855 50

[3-(3-{[(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carbonyl]-amino}-4-methyl-phenyl)-5-methyl- pyrazol-1-yl]-acetic acid ethyl ester7.145 51

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid (2-methyl-5-pyrimidin-2-yl-phenyl)- amide 7.87 52

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid (2-methyl-5-pyrimidin-5-yl-phenyl)- amide 6.425 53

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(2-methyl-pyrimidin-4-yl)- phenyl]-amide 7.325 54

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(2-methyl-pyridin-4-yl)- phenyl]-amide 7.045 55

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(5-chloro-3-oxo-2,3-dihydro-pyridazin-4-yl)-2-methyl-phenyl]-amide 7.54 56

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(3-oxo-2,3-dihydro- pyridazin-4-yl)-phenyl]-amide 8.25657

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid (2-methyl-5-thiazol-4-yl-phenyl)-amide 8.06 58

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(2-methyl-thiazol-4-yl)- phenyl]-amide 7.87 59

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid (2-methyl-5-pyridin-4-yl-phenyl)-amide 7.22 60

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(4-ethyl-5-methyl-4H-[1,2,4]triazol-3-yl)-2-methyl-phenyl]-amide 6.535 61

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-((S)-2,3- dihydroxy-propyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-phenyl}-amide 7.255 62

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(5-cyclopropyl-1H-pyrazol-3-yl)-2- methyl-phenyl]-amide 6.935 63

(S)-4-(3-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(1-methyl-1H-pyrazol-3- yl)-phenyl]-amide 7.965 64

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-((R)-2,3- dihydroxy-propyl)-5-methyl-1H-pyraozl-3-yl]-2-methyl-phenyl}-amide 7.585 65

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(1-methyl-1H-pyrazol-3- yl)-phenyl]-amide 7.705 66

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid (2-methyl-5-[1,2,4]triazol-4-yl-phenyl)- amide 5.55 67

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(4-ethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-phenyl]- amide 7.575 68

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin- 2-yl)-phenyl]-amide 7.01 69

(S)-4-(3-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-phenyl}-amide 7.92 70

(S)-4-(3-Fluoro-phenyl)-1-methyl-6- ox-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl- phenyl}-amide 7.72 71

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-amide 8.395 72

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-amide 7.8367 73

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-((R)-2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl]-2- methyl-phenyl}-amide 7.255 74

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-((S)-2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl]-2- methyl-phenyl}-amide 7.47 75

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[1-((R)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl]-2- methyl-phenyl}-amide 7.72 76

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-((R)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol- 3-yl]-2-methyl-phenyl}-amide 7.4577

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[4-((R)-2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl]-2-methyl-phenyl}-amide 7.5367 78

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(3-methyl-6-oxo-6H- pyridazin-1-yl)-phenyl]-amide 7.3179

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(6-methyl-pyrazin-2-yl)- phenyl]-amide 6.58 80

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(4-methyl-pyrimidin-2-yl)- phenyl]-amide 7.315 81

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)- phenyl]-amide 7.94 82

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(6-oxo-1,6-dihydro-pyrazin- 2-yl)-phenyl]-amide 5.39583

[3-(3-{[(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carbonyl]-amino}-4-methyl-phenyl)-5-methyl- pyrazol-1-yl]-acetic acid 6.335 84

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[1-(2-hydroxy-ethyl)-1H-pyrazol-3- yl]-2-methyl-phenyl}-amide7.53 85

4-(3,4-Difluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[1-(2-hydroxy-ethyl)-5-methyl-1H-pyraozl-3-yl]-2-methyl-phenyl}-amide 7.375 86

(S)-4-(3-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)- phenyl]-amide 7.62 87

(S)-4-(3-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-amide 7.884 88

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(6-oxo-6H-pyridazin-1-yl)- phenyl]-amide 89

(S)-4-(3-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(6-oxo-6H-pyridazin-1-yl)- phenyl]-amide 7.53 90

(S)-4-(3-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-((R)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol- 3-yl]-2-methyl-phenyl}-amide 7.2 91

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[1-((S)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl]-2- methyl-phenyl}-amide 7.15 92

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-((S)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol- 3-yl]-2-methyl-phenyl}-amide 6.61593

(S)-4-(3-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[2-(2-hydroxy-ethyl)-3-oxo-2,3-dihydro-pyridazin-4-yl]-2- methyl-phenyl}-amide 7.5 94

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[2-(2-hydroxy-ethyl)-3-oxo-2,3-dihydro-pyridazin-4-yl]-2- methyl-phenyl}-amide 7.8 95

4-(3,5-Difluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-phenyl}-amide 7.85 96

(S)-4-(3-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(6-methyl-pyridazin-3-yl)- phenyl]-amide 7.48 97

(S)-4-(3-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid (2-methyl-5-pyrimidin-2-yl-phenyl)- amide 7.09 98

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-amide 6.52 99

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(6-oxo-1,6-dihydro- pyridazin-3-yl)-phenyl]-amide 7.515100

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin- 2-yl]-2-methyl-phenyl}-amide7.5 101

(S)-4-(3-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin- 2-yl]-2-methyl-phenyl}-amide7.57 102

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(5-trifluoromethyl-1H- pyrazol-3-yl)-phenyl]-amide 5.77103

(S)-4-(3-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-((S)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol- 3-yl]-2-methyl-phenyl}-amide 7.1104

(S)-4-(3-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[2-((R)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl]-2-methyl-phenyl}-amide 7.8 105

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[2-((R)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl]-2-methyl-phenyl}-amide 7.57 106

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[2-((R)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4- yl]-2-methyl-phenyl}-amide 7.885107

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [5-(3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-phenyl]-amide 6.81 108

(S)-4-(3-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [5-(3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-phenyl]-amide 7.145 109

(S)-4-(3-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-amide 8.045 110

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(6-oxo-6H- pyridazin-1-yl)-phenyl]-amide7.17 111

(S)-4-(3-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-pyrazol-3-yl]-2- methyl-phenyl}-amide 6.895 112

(S)-4-(3-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl]-2-methyl-phenyl}- amide 7.645 113

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [5-(1H-pyrazol-3-yl)-2-trifluoromethyl- phenyl]-amide 7.173 114

4-(3-Chloro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylic acid{5-[1-(2-hydroxy-ethyl)-1H-pyrazol-3- yl]-2-methyl-phenyl}-amide 7.56115

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {2-chloro-5-[1-(2- hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-phenyl}-amide 7.04 116

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(2-oxo-1,2-dihydro-pyridin-3-yl)-phenyl]-amide 7.565 117

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [5-(6-methoxy- pyridazin-3-yl)-2-methyl-phenyl]-amide7.22 118

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(6-oxo-1,6-dihydro-pyridazin-3-yl)-phenyl]-amide 6.585 119

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid (5-{1-[(2-dimethylamino- ethylcarbamoyl)-methyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenyl)-amide 7.685 120

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(1-methyl- 2-oxo-1,2-dihydro-pyridin-3-yl)-phenyl]-amide 7.855 121

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {5-[1-(2-hydroxy-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-methyl- phenyl}-amide 7.385 122

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(5-methyl-2-oxo-2H- pyridin-1-yl)-phenyl]-amide 8.26123

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-fluoro-5-(3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-amide 7.58 124

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [5-(2,4-dioxo-3,4- dihydro-2H-pyrimidin-1-yl)-2-methyl-phenyl]-amide 6.44 125

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [4-chloro-2-methyl-5-(6-oxo-6H- pyridazin-1-yl)-phenyl]-amide 7.606126

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-((R)-2-hydroxy-3-methoxy-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-2-methyl-phenyl}-amide 7.615 127

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [4-chloro-2-methyl-5-(2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]- amide 7.843 128

(S)-1-Dimethylcarbamoylmethyl-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro- pyridine-3-carboxylic acid[2-methyl-5- (2-methyl-3-oxo-2,3-dihydro-pyridazin- 4-yl)-phenyl]-amide7.195 129

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1- yl)-phenyl]-amide 7.945 130

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [4-fluoro-2-methyl-5-(2-methyl-3-oxo-2,3-dihydro-pyridazin-4- yl)-phenyl]-amide 7.864 131

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [5-(4-ethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2- methyl-phenyl]-amide 7.42 132

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1- yl)-phenyl]-amide 6.015 133

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-phenyl]- amide 7.24 134

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {5-[1-(2-hydroxy-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl]-2- methyl-phenyl}-amide 6.42 135

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(4-methyl-6-oxo-6H- pyridazin-1-yl)-phenyl]-amide 7.655136

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(4-methyl-6-oxo-6H-pyridazin-1-yl)-phenyl]-amide 7.515 137

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-fluoro-5-(5-methyl- 1H-pyrazin-3-yl)-phenyl]-amide6.39 138

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [4-fluoro-2-methyl-5-(6-oxo-6H- pyridazin-1-yl)-phenyl]-amide 139

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [4-fluoro-2-methyl-5-(1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)- phenyl]-amide 7.83 140

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(5-methyl-2-oxo-2H-pyridin-1-yl)-phenyl]-amide 7.18 141

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-fluoro-5-(2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)- phenyl]-amide 7.36 142

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-fluoro-5-(2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-amide 8.2 143

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [4-fluoro-2-methyl-5-(4-methyl-6-oxo-6H-pyridazin-1-yl)-phenyl]-amide 7.455 144

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [2-fluoro-5-(6-oxo-6H-pyridazin-1-yl)- phenyl]-amide 145

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [4-fluoro-2-methyl-5-(4-methyl-6-oxo-6H-pyridazin-1-yl)- phenyl]-amide 7.265 146

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-fluoro-5-(6-oxo-6H- pyridazin-1-yl)-phenyl]-amide5.74 147

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid {4-fluoro-5-[1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl- phenyl}-amide 148

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {4-fluoro-5-[1-(2- hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-phenyl}-amide 7.41 149

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [4-fluoro-2-methyl-5-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)- phenyl]-amide 150

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6- tetrahydro-pyridine-3-carboxylicacid [4-fluoro-2-methyl-5-(2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]- amide 151

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [4-fluoro-2-methyl-5-(6-oxo-6H-pyridazin-1-yl)-phenyl]-amide 152

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [4-fluoro-2-methyl-5-(1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)- phenyl]-amide 153

(S)-4-(4-Fluoro-phenyl)-1-(2-hydroxy- ethyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-methyl-5-(4-methyl-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl)-phenyl]-amide154

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [5-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-fluoro- phenyl]-amide 155

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [3-fluoro-2-methyl-5-(2-methyl-3-oxo-2,3-dihydro-pyridazin-4- yl)-phenyl]-amide 156

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [3-fluoro-2-methyl-5-(3-oxo-2,3-dihydro-pyridazin-4-yl)- phenyl]-amide 157

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {4-fluoro-5-[1-((R)-2-hydroxy-3-methoxy-propyl)-2-oxo-1,2-dihydro-pyridin-3-yl]-2-methyl-phenyl}- amide 158

(S)-4-(4-Fluoro-phenyl)-1-methyl-6- oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid [2-ethyl-5-(2-methyl-3- oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-amide 159

Acetic acid (R)-2-[2-(3-{[(S)-4-(4-fluoro-phenyl)-1-methyl-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carbonyl]-amino}- 4-methyl-phenyl)-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl]-1- methoxymethyl-ethyl ester

Synthesis

Compounds of the present invention can be made by a variety of methodsdepicted in the illustrative synthetic reaction schemes shown anddescribed below.

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1991, Volumes 1-15; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 1991, Volumes 1-40. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C.

Scheme A below illustrates one synthetic procedure usable to preparespecific compounds of formula I, wherein X is halo and may be the sameor different upon each occurrence, Y is a leaving group, and A, p, q,R¹, R⁶ and R¹¹ are as defined herein.

In step 1 of Scheme A, a Grignard reaction is carried out whereinnicotinic acid compound a is reacted with phenyl magnesium halidecompound b to afford a phenyl dihydropyridone carboxylic acid compoundc. In many embodiments, for example, commercially available6-chloro-nicotinic acid may be used for compound a. Numerous phenylmagnesium bromide compounds are readily prepared by well knowntechniques and may be used for compound b.

In step 2, dihydropyridone compound c is optionally modified tointroduce a leaving group Y to the acyl moiety of compound d. Carboxylicacid derivative compound d may comprise, for example, a carboxylic acidhalide, a carboxylate ester or a carboxylic acid anhydride, dependingupon the nature of leaving group Y. In many embodiments Y is halo suchas chloro, such that compound d may be prepared by treatment ofcarboxylic acid compound c with oxalyl chloride, thionyl chloride, orlike halogenating agent.

In step 3, an amide coupling reaction is carried out wherein an anilinecompound e is reacted with compound d, to afford dihydropyridoneamidecompound f, which is a compound of formula I in accordance with theinvention. Numerous aniline compounds e are commercially available orare readily prepared using synthetic procedures well known in the art.Such aniline compounds may in many embodiments be made by reduction ofthe corresponding aryl nitro compounds, as illustrated in theexperimental examples below. In the procedure of Scheme A, anilinecompound a is shown as a substituted phenyl compound. Other aryl aminessuch as naphthylamines may be used as well with the invention.

Many variations on the procedure of Scheme A are possible and willsuggest themselves to those skilled in the art. For example, in certainembodiments step 2 may be omitted, and other amide coupling reactionprocedures using EDCI, HATU, BOP, PyBOP or the like, may be used in step3. Specific details for producing compounds of the invention aredescribed in the Examples section below.

Utility

The compounds of the invention are usable for the treatment of a widerange of inflammatory diseases and conditions such as arthritis,including but not limited to, rheumatoid arthritis,spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis, osteoarthritis, gouty arthritisand other arthritic conditions. The subject compounds would be usefulfor the treatment of pulmonary disorders or lung inflammation, includingadult respiratory distress syndrome, pulmonary sarcoidosis, asthma,silicosis, and chronic pulmonary inflammatory disease.

The compounds of the invention are also expected to find utility asanalgesics in the treatment of diseases and conditions associated withpain from a wide variety of causes, including, but not limited to,inflammatory pain such as pain associated with arthritis (includingrheumatoid arthritis and osteoarthritis), surgical pain, visceral pain,dental pain, premenstrual pain, central pain, pain due to burns,migraine or cluster headaches, nerve injury, neuritis, neuralgias,poisoning, ischemic injury, interstitial cystitis, cancer pain, viral,parasitic or bacterial infection, post-traumatic injuries (includingfractures and sports injuries), and pain associated with functionalbowel disorders such as irritable bowel syndrome.

Further, compounds of the invention are useful for treating respiratorydisorders, including chronic obstructive pulmonary disorder (COPD),asthma, bronchospasm, and the like.

Additionally, compounds of the invention are useful for treatinggastrointestinal disorders, including Irritable Bowel Syndrome (IBS),Inflammatory Bowel Disease (IBD), biliary colic and other biliarydisorders, renal colic, diarrhea-dominant IBS, pain associated with GIdistension, and the like.

The compounds of the invention are also useful for the treatment ofmuscular sclerosis and diabetes.

Administration and Pharmaceutical Composition

The invention includes pharmaceutical compositions comprising at leastone compound of the present invention, or an individual isomer, racemicor non-racemic mixture of isomers or a pharmaceutically acceptable saltor solvate thereof, together with at least one pharmaceuticallyacceptable carrier, and optionally other therapeutic and/or prophylacticingredients.

In general, the compounds of the invention will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. Suitable dosageranges are typically 1-500 mg daily, preferably 1-100 mg daily, and mostpreferably 1-30 mg daily, depending upon numerous factors such as theseverity of the disease to be treated, the age and relative health ofthe subject, the potency of the compound used, the route and form ofadministration, the indication towards which the administration isdirected, and the preferences and experience of the medical practitionerinvolved. One of ordinary skill in the art of treating such diseaseswill be able, without undue experimentation and in reliance uponpersonal knowledge and the disclosure of this application, to ascertaina therapeutically effective amount of the compounds of the presentinvention for a given disease.

Compounds of the invention may be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral(including intramuscular, intraarterial, intrathecal, subcutaneous andintravenous) administration or in a form suitable for administration byinhalation or insufflation. The preferred manner of administration isgenerally oral using a convenient daily dosage regimen which can beadjusted according to the degree of affliction.

A compound or compounds of the invention, together with one or moreconventional adjuvants, carriers, or diluents, may be placed into theform of pharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. Formulations containing about one (1) milligram ofactive ingredient or, more broadly, about 0.01 to about one hundred(100) milligrams, per tablet, are accordingly suitable representativeunit dosage forms.

The compounds of the invention may be formulated in a wide variety oforal administration dosage forms. The pharmaceutical compositions anddosage forms may comprise a compound or compounds of the presentinvention or pharmaceutically acceptable salts thereof as the activecomponent. The pharmaceutically acceptable carriers may be either solidor liquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substances which may also act as diluents,flavouring agents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial. In powders, the carrier generally is a finely divided solidwhich is a mixture with the finely divided active component. In tablets,the active component generally is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired. The powders and tablets preferably contain fromabout one (1) to about seventy (70) percent of the active compound.Suitable carriers include but are not limited to magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier, providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is in association with it. Similarly, cachets and lozenges areincluded. Tablets, powders, capsules, pills, cachets, and lozenges maybe as solid forms suitable for oral administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions maybe prepared in solutions, for example, in aqueous propylene glycolsolutions or may contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Solid form preparations include solutions,suspensions, and emulsions, and may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compounds of the invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatine andglycerine or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the invention may be formulated for administration assuppositories. A low melting wax, such as a mixture of fatty acidglycerides or cocoa butter is first melted and the active component isdispersed homogeneously, for example, by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and to solidify.

The compounds of the invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. Thesolutions or suspensions are applied directly to the nasal cavity byconventional means, for example, with a dropper, pipette or spray. Theformulations may be provided in a single or multidose form. In thelatter case of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

The compounds of the invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration.

The compound will generally have a small particle size for example ofthe order of five (5) microns or less. Such a particle size may beobtained by means known in the art, for example by micronization. Theactive ingredient is provided in a pressurized pack with a suitablepropellant such as a chlorofluorocarbon (CFC), for example,dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatine orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylazacycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Other suitable pharmaceutical carriers and their formulations aredescribed in Remington: The Science and Practice of Pharmacy 1995,edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton,Pa. Representative pharmaceutical formulations containing a compound ofthe present invention are described below.

EXAMPLES

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Unless otherwise stated, all temperatures including melting points(i.e., MP) are in degrees Celsius (° C.). It should be appreciated thatthe reaction which produces the indicated and/or the desired product maynot necessarily result directly from the combination of two reagentswhich were initially added, i.e., there may be one or more intermediateswhich are produced in the mixture which ultimately leads to theformation of the indicated and/or the desired product. The followingabbreviations may be used in the Preparations and Examples.

ABBREVIATIONS

-   -   BETBDMS 2-bromoethoxy tertbutyldimethylsilane    -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCM dichloromethane/methylene chloride    -   DIPEA diisopropyl ethylamine (Hunig's base)    -   DME 1,2-dimethoxyethane (glyme)    -   DMF N,N-dimethylformamide    -   DMFDMA N,N-dimethylformamide dimethyl acetal    -   DMSO dimethyl sulfoxide    -   DMAP 4-dimethylaminopyridine    -   dppf 1,1′-Bis(diphenylphosphino)ferrocene    -   EDCI 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide    -   EtOAc ethyl acetate    -   EtOH ethanol    -   gc gas chromatography    -   HATU 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium        hexafluorophosphate Methanaminium    -   HMPA hexamethylphosphoramide    -   HOBt N-Hydroxybenzotriazole    -   hplc high performance liquid chromatography    -   IPA isopropanol    -   IPBAPE isopropenylboronic acid pinacol ester    -   mCPBA m-chloroperbenzoic acid    -   MeCN acetonitrile    -   NMM N-methyl morpholine    -   NMP N-methylpyrrolidinone    -   Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0)    -   TBAF tetra-n-butyl ammonium fluoride    -   tBDMSiCl tert-butyl-dimethylsilyl chloride    -   tBDMSIBr tert-butyl-dimethylsilyl bromide    -   TEA triethylamine    -   THF tetrahydrofuran    -   LDA lithium diisopropylamine    -   TBDMS tert-butyl dimethylsilyl chloride    -   TLC thin layer chromatography    -   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene

Preparation 14-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid

The synthetic procedure used in this preparation is outlined in SchemeB.

4-Fluorophenylmagnesium bromide (2M in THF; 130 ml) was added dropwiseat 0° C. to a stirring solution of 6-chloronicotinic acid (12.92 g) in150 mL of THF. After the addition was complete the reaction mixture wasstirred at ambient temperature for 16 hours. The reaction mixture wascooled to −60° C. and acetic acid (105 ml) was added dropwise, resultingin formation of a solid. After the addition was complete the reactionmixture was warmed to ambient temperature. The reaction mixture was thencooled to 0° C. and quenched by addition of saturated aqueous ammoniumchloride solution. The mixture was partitioned between water and ethylacetate, and the organic layer was separated, washed with water andbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was dissolved in hot ethyl acetate. Upon standinga solid precipitate formed, which was collected and dried to give 10.04g of 4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid as a white solid.

Preparation 2 Chiral Separation of (R) and (S)4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid

The (R) and (S) isomers of4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acidwere separated using an R,R Whelk-O1 (Regis Technologies) chiral column,30 mm I.D.×250 mm length, designed for use with supercritical CO₂ fluidchromatography. Racemic4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acidwas dissolved in a 5% THF/95% methanol solution to 100 mg/mlconcentration. The solution was filtered and warmed to 40° C. Thesolution was injected onto the column in 1.7 mL increments and elutedwith 35% methanol (HPLC grade), 65% supercritical CO₂ at 40° C. The (S)isomer was recovered from the first fraction ([alpha]=+197.3° (CHCl₃c=0.629), mp. 210-212° C.) and the (R) isomer was recovered from thesecond fraction ([alpha]=−197.4° (CHCl₃ c=0.618), mp. 213-215° C.).Stacked injections were jused with a single run time of seven minutes.

Preparation 33-(5-Amino-2-fluoro-4-methyl-phenyl)-5-methyl-pyrazole-1-carboxylic acidbenzyl ester

The synthetic procedure used in this preparation is outlined in SchemeC.

Step 1 1-(2-Fluoro-4-methyl-5-nitro-phenyl)-ethanone

Copper (II) nitrate (3.175 g) was added portion wise to a roomtemperature solution of 1-(2-fluoro-4-methyl-phenyl)-ethanone (2.74 g)in chloroform (30 ml) and Trifluoroacetic anhydride. The mixture washeated at 60° C. for 30 minutes then cooled to room temperature andadded to ice. The mixture was extracted with methylene chloride, and theorganic layer was washed with water and brine, dried (Na₂SO₄), filteredand concentrated under reduced pressure to give 3.17 g of1-(2-Fluoro-4-methyl-5-nitro-phenyl)-ethanone as a reddish oil, whichwas used directly without further purification.

Step 2 1-(5-Amino-2-fluoro-4-methyl-phenyl)-ethanone

1-(2-Fluoro-4-methyl-5-nitro-phenyl)-ethanone (3.17 g) in ethanol (10ml) was hydrogenated over Pd/C (200 mg) under balloon pressure overnight. The mixture was filtered and the filtrate was concentrated underreduced pressure to a grey solid that was recrystallized (EtOAc Hexane)to give 1.625 g of 1-(5-amino-2-fluoro-4-methyl-phenyl)-ethanone as anoff-white powder.

Step 3 (5-Acetyl-4-fluoro-2-methyl-phenyl)-carbamic acid tert-butylester

“BOC” anhydride (2.451 g) was added in one portion to a 0° C. solutionof 1-(5-amino-2-fluoro-4-methyl-phenyl)-ethanone (1.625 g) and DMAP (20mg) in THF (10 ml). The reaction mixture was stirred at room temperaturefor 20 hours, then concentrated under reduced pressure. “Flashchromatography” 0 to 30% EtOAc in hexanes gave(5-Acetyl-4-fluoro-2-methyl-phenyl)-carbamic acid tert-butyl ester (2.45g) as a white solid.

Step 4 [4-Fluoro-2-methyl-5-(5-methyl-1H-pyrazol-3-yl)-phenyl]-carbamicacid tert-butyl ester

A solution of (5-Acetyl-4-fluoro-2-methyl-phenyl)-carbamic acidtert-butyl ester (425 mg) and (1,1-dimethoxy-ethyl)-dimethyl-amine (653mg) in DMF (2 ml) was heated at 90° C. for 3 hours, then cooled to roomtemperature. Solvent was removed under reduced pressure, and the residuewas dissolved in a mixture of EtOH (25 ml) and THF (5 ml). The mixturewas cooled to 0° C., and hydrazine hydrate (5 ml) at 0° C. was added.The mixture was stirred for 16 hours at room temperature, thenconcentrated under reduced pressure. The residue was purified by “flashchromatography” (0 to 30% EtOAc in hexanes) to give 370 mg of[4-fluoro-2-methyl-5-(5-methyl-1H-pyrazol-3-yl)-phenyl]-carbamic acidtert-butyl ester.

Step 53-(5-tert-Butoxycarbonylamino-2-fluoro-4-methyl-phenyl)-5-methyl-2H-pyrazole-1-carboxylicacid benzyl ester

Benzylchloroformate (104 mg) was added dropwise to a room temperaturesolution of[4-fluoro-2-methyl-5-(5-methyl-1H-pyrazol-3-yl)-phenyl]-carbamic acidtert-butyl ester and DIPEA in CH₂Cl₂ (2 ml). The mixture was stirred atroom temperature for one hour, and then 10% aqueous citric acid solutionwas added. The organic layer was separated dried (Na₂SO₄), filtered andconcentrated under reduced pressure. “Flash chromatography” of theresidue (0 to 20% EtOAc in hexanes) gave 210 mg of3-(5-tert-Butoxycarbonylamino-2-fluoro-4-methyl-phenyl)-5-methyl-2H-pyrazole-1-carboxylicacid benzyl ester as a white solid.

Step 63-(5-Amino-2-fluoro-4-methyl-phenyl)-5-methyl-pyrazole-1-carboxylic acidbenzyl ester

3-(5-tert-Butoxycarbonylamino-2-fluoro-4-methyl-phenyl)-5-methyl-2H-pyrazole-1-carboxylicacid benzyl ester (320 mg) was hydrogenated using 10% Pd/C (40 mg)following the procedure of step 2 to give3-(5-amino-2-fluoro-4-methyl-phenyl)-5-methyl-pyrazole-1-carboxylic acidbenzyl ester (205 mg) as a white solid.

Preparation 4 2-Methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine

The synthetic procedure used in this preparation is outlined in SchemeD.

Step 1 5-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole

A solution of 1-(4-methyl-3-nitro-phenyl)-ethanone and(1,1-dimethoxy-ethyl)-dimethyl-amine in DMF was heated at 90° C. for 3hours, then cooled to room temperature. Solvent was removed underreduced pressure, and the residue was dissolved in a mixture of EtOH (25ml) and THF (5 ml). The mixture was cooled to 0 oC, and hydrazinehydrate (5 ml) at 0° C. was added. The mixture was stirred for 16 hoursat room temperature, then concentrated under reduced pressure. Theresidue was purified by “flash chromatography” (0 to 30% EtOAc inhexanes) to give 8.5 g of5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole as a yellowish solid,which was recrystallized from EtOAc to give 8.2 g of yellow powder.

Step 2 2-Methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine

5-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole (8.2 g) was dissolvedin ethanol and Palladium (10%) on activated carbon was added. Themixture was subject to barometric hydrogenation under balloon pressurefor five hours at room temperature. The mixture was filtered and thefiltrate was concentrated under reduced pressure to give 414 mg of crude2-methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine as a white solid,which was used directly without further purification.

Preparation 55-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenylamine

The synthetic procedure used in this preparation is outlined in SchemeE.

Step 11-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole

A solution of 5-Methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole,tert-butyl-dimethylsilyl bromide, Cs₂CO₃ and NaI in NMP was heated in amicrowave oven at 100° C. for 1 hour, and then cooled to roomtemperature. The reaction mixture was diluted with EtOAc, washed withwater and brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified by “flash chromatography” (0to 30% EtOAc in hexanes to give 867 mg of1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazoleas an oil that also contained1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-methyl-5-(4-methyl-3-nitro-phenyl)-1H-pyrazoleas a minor product.

Step 25-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenylamine

1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-3-(4-methyl-3-nitro-phenyl)-1H-pyrazole(867 mg) was dissolved in ethanol and Palladium (10%) on activatedcarbon was added. The mixture was subject to barometric hydrogenationunder balloon pressure for five hours at room temperature. The mixturewas filtered and the filtrate was concentrated under reduced pressure togive crude5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenylamineas a white solid, which was used directly without further purification.

Example 1(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid[4-chloro-5-(2-hydroxy-ethoxy)-2-methyl-phenyl]-amide

The synthetic procedure used in this preparation is outlined in SchemeF.

Oxalylchloride (76 mg) was added to a room temperature solution of(S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid (94 mg) in dichloromethane (10 ml) containing 2 drops of DMF. Thereaction mixture was stirred for 30 minutes and then solvent was removedunder reduced pressure to give crude(S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid chloride, which was not removed from the flask. Dichloromethane (10mL) was added, and the dichloromethane solution of the acid chloride wasadded to a stirring solution of2-methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenylamine (75 mg) and triethylamine (0.97 g) in dichloromethane (30 ml). The reaction was stirred at0° C. for 10 minutes, then at ambient temperature for 20 minutes.Solvent was removed under reduced pressure and the residue was purifiedby flash chromatography (0 to 5% methanol in dichloromethane) to give 38mg of(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid [2-methyl-5-(5-methyl-2H-pyrazol-3-yl)-phenyl]-amide as a so lid.

Additional compounds prepared by the above procedure are shown in Table1.

Example 2

(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid{5-[1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-phenyl}-amide

The synthetic procedure used in this preparation is outlined in SchemeG.

Step1(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid(5-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenyl)-amide

A solution of(S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid (138 mg), N,N-Diisopropylethylamine (155 mg) and HATU (152 mg) inNMP (1 ml) was stirred at room temperature for 10 minutes. A solution of5-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenylamine(94 mg) in NMP (1 ml) was added, and the reaction mixture was stirredfor 16 hours at room temperature. The reaction mixture was poured intowater and extracted with EtOAc. The organic layer was washed with waterand brine, dried (Na₂SO₄), filtered and concentrated under reducedpressure. The residue was purified by “flash chromatography” (0 to 5%MeOH in CH₂Cl₂) to give 62.2 mg of(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid(5-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenyl)-amideas an amorphous solid.

Step 2(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid{5-[1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-phenyl}-amide

A solution tetrabutylammonium fluoride (1M in THF) was added drop wiseto a 0° C. solution of(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid(5-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-pyrazol-3-yl}-2-methyl-phenyl)-amide(66 mg) in THF. The mixture was stirred at 0° C. for five minutes andthen stirred at room temperature for 18 hours. The mixture waspartitioned between water and EtOAc. The organic layer was washed withwater and brine, dried over Na₂SO₄, filtered, and concentrated todryness under reduced pressure. Purification of the crude product byflash chromatography (0 to 8% CH₃OH in CH₂Cl₂) gave 24 mg of(S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid{5-[1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl]-2-methyl-phenyl}-amideas a solid, MS (M+H)=419.

Additional compounds made by the above procedure are shown in Table 1.

Example 3(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid [4-fluoro-2-methyl-1H-pyrazol-3-yl]-phenyl]-amide

The synthetic procedure used in this preparation is outlined in SchemeH.

Step 13-(2-Fluoro-5-{[(S)-4-(4-fluoro-phenyl)-6-oxo-1,2,5,6-tetrahydro-pyridine-3-carbonyl]-amino}-4-methyl-phenyl)-5-methyl-pyrazole-1-carboxylicacid benzyl ester

3-(5-Amino-2-fluoro-4-methyl-phenyl)-5-methyl-pyrazole-1-carboxylic acidbenzyl ester (205 mg) and(S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid (94 mg) were converted to3-(2-fluoro-5-{[(S)-4-(4-fluoro-phenyl)-6-oxo-1,2,5,6-tetrahydro-pyridine-3-carbonyl]-amino}-4-methyl-phenyl)-5-methyl-pyrazole-1-carboxylicacid benzyl ester (290 mg) following the procedure of step 1 of Example2.

Step 2(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid [4-fluoro-2-methyl-1H-pyrazol-3-yl]-phenyl]-amide

3-(2-Fluoro-5-{[(S)-4-(4-fluoro-phenyl)-6-oxo-1,2,5,6-tetrahydro-pyridine-3-carbonyl]-amino}-4-methyl-phenyl)-5-methyl-pyrazole-1-carboxylicacid benzyl ester (290 mg) and 10% Pd/C in ethanol (5 ml) washydrogenated under balloon pressure to give(S)-4-(4-Fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylicacid [4-fluoro-2-methyl-1H-pyrazol-3-yl]-phenyl]-amide (210 mg); MS(M+H)=423.

Additional compounds prepared by the above procedure are shown in Table1.

Example 4 Formulations

Pharmaceutical preparations for delivery by various routes areformulated as shown in the following Tables. “Active ingredient” or“Active compound” as used in the Tables means one or more of theCompounds of Formula I.

Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0% Lactose 79.5% Magnesium stearate 0.5%

The ingredients are mixed and dispensed into capsules containing about100 mg each; one capsule would approximate a total daily dosage.

Composition for Oral Administration Ingredient % wt./wt. Activeingredient 20.0% Magnesium stearate 0.5% Crosscarmellose sodium 2.0%Lactose 76.5% PVP (polyvinylpyrrolidine) 1.0%

The ingredients are combined and granulated using a solvent such asmethanol. The formulation is then dried and formed into tablets(containing about 20 mg of active compound) with an appropriate tabletmachine.

Composition for Oral Administration Ingredient Amount Active compound1.0 g Fumaric acid 0.5 g Sodium chloride 2.0 g Methyl paraben 0.15 gPropyl paraben 0.05 g Granulated sugar 25.5 g Sorbitol (70% solution)12.85 g Veegum K (Vanderbilt Co.) 1.0 g Flavoring 0.035 ml Colorings 0.5mg Distilled water q.s. to 100 ml

The ingredients are mixed to form a suspension for oral administration.

Parenteral Formulation Ingredient % wt./wt. Active ingredient 0.25 gSodium Chloride qs to make isotonic Water for injection 100 ml

The active ingredient is dissolved in a portion of the water forinjection. A sufficient quantity of sodium chloride is then added withstirring to make the solution isotonic. The solution is made up toweight with the remainder of the water for injection, filtered through a0.2 micron membrane filter and packaged under sterile conditions.

Suppository Formulation Ingredient % wt./wt. Active ingredient 1.0%Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

Topical Formulation Ingredients Grams Active compound 0.2-2 Span 60 2Tween 60 2 Mineral oil 5 Petrolatum 10 Methyl paraben 0.15 Propylparaben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. 100

All of the ingredients, except water, are combined and heated to about60° C. with stirring. A sufficient quantity of water at about 60° C. isthen added with vigorous stirring to emulsify the ingredients, and waterthen added q.s. about 100 g.

Nasal Spray Formulations

Several aqueous suspensions containing from about 0.025-0.5 percentactive compound are prepared as nasal spray formulations. Theformulations optionally contain inactive ingredients such as, forexample, microcrystalline cellulose, sodium carboxymethylcellulose,dextrose, and the like. Hydrochloric acid may be added to adjust pH. Thenasal spray formulations may be delivered via a nasal spray metered pumptypically delivering about 50-100 microliters of formulation peractuation. A typical dosing schedule is 2-4 sprays every 4-12 hours.

Example 5 Intracellular Calcium Flux (FLIPR) Assay Compound and ReagentPreparation

Stock solutions of compounds were prepared from powders as a 10 mM DMSOstock solution. These solutions were stored at RT during the two weekperiod of these experiments to prevent freeze-thaw of the DMSO stocks.The DMSO stocks were added to the appropriate assay buffer at aconcentration of 10 μM, and then diluted serially to the finalconcentrations that were tested. No observable precipitate was formed atany time during this process. The aqueous solutions of compounds as wellas ATP (Sigma A7699) and BzATP (Sigma B6396) were prepared fresh foreach day of experiment.

Cell Culture: 1321N1-hP2X₇ and HEK293-rP2X₇

1321N1 cells stably expressing the full length human P2X₇ gene(1321N1-hP2X₇) and HEK293 cells stably expressing the full length ratP2X₇ gene (HEK293-rP2X₇) were obtained from the Roche Cell CultureFacility. 1321N1-hP2X₇ cells were grown in Dulbecco's Modified Eagle'sMedium (DMEM) high glucose supplemented with 10% FBS and 250 μg/mL G418.HEK293-rP2X₇ cells were grown in DMEM/F-12 supplemented with 10% FBS, 1mM CaCl₂, 2 mM MgCl₂, 2 mM L-Glutamine and 500 μg/ml G418. Cells weresplit such that they never became >70% confluent.

Intracellular Calcium Flux (FLIPR)

On the day prior to the experiment, 1321N1-hP2X₇ or HEK293-rP2X₇ cellswere released into suspension with calcium-free PBS+Versene and washedby centrifugation with calcium-free PBS to remove the Versene. Cellswere resuspended in growth medium at a density of 2.5×10⁵ cells/mL andseeded into black walled, clear bottom 96 well plates (50,000cells/well) approximately 18 hr prior to intracellular calcium fluxexperiments.

On the day of the experiment, plates were washed with FLIPR buffer(calcium- and magnesium-free Hank's Balanced Salt Solution (HBSS)supplemented with 10 mM Hepes, 2.5 mM probenecid and 2 mM calciumchloride) using a BIO-TEK 96 channel plate washer and incubated with 2mM fluo-3 dye at 37° C. for one hr. The dye was then removed by platewashing and the cells were allowed to equilibrate for 20 min at roomtemperature with antagonist or vehicle (FLIPR buffer). Agonist (100 μMBzATP final concentration for hP2X₇; 5 μM BzATP final concentration orrP2X₇) was added online with the FLIPR and fluorescence measurementsmade at 1 sec intervals for 60 sec followed by 3 sec intervals for afurther 4 min (5 min total). A final addition of 5 μM ionomycin was madeand the maximal BzATP-evoked fluorescence normalized to the maximalionomycin-evoked fluorescence.

Example 6 Human Whole Blood IL-1β Release Assay Compound & ReagentPreparation

10 mM stock solutions of compounds in DMSO (Sigma D2650) were preparedand used either fresh or after storage at −20° C. Appropriate (200×)serial dilutions of the compounds were made in DMSO, then freshlydiluted 1 to 20 (10×) with Dulbecco's phosphate buffered saline (DPBS;Mediatech Inc., 21-030), such that final DMSO concentration in the bloodalways equaled 0.5%.

30 mM ATP (Sigma A7699) was prepared immediately before use in 50 mMHEPES (Gibco 15630) and the pH adjusted to 7.2 with 1M sodium hydroxide.

Blood Donors

Human blood donors were medication free and restricted from utilizingalcohol or caffeine for at least the 24 hr preceding collection. Theblood was collected into sodium heparin vacutainer tubes and used thesame day.

Assay Method

The OptEIA Human IL-113 ELISA Set, OptEIA Coating Buffer, Assay Diluentand TMB Substrate Reagent Set used in the assay were commerciallyobtained from BD Pharmingen. Blood was diluted 1:1 with Dulbecco's PBS,LPS (Escherichia Coli 0127:B8, Sigma L3129) added to a finalconcentration of 25 ng/mL and incubated for 2 hr at 37° C. 48 μL of thisLPS primed blood was added to 6 μL of the 10× compound in 5% DMSO/PBS inthe appropriate well of a 96-well polypropylene plate. The blood andcompound were mixed and allowed to incubate for 30 min at 37° C. 6 μl of30 mM ATP was added to the LPS-primed blood+compound, mixed thoroughlyand incubated for a further 30 min at 37° C. 96 μL of ELISA assay bufferwas added to each well and the plate centrifuged at 4° C. 1,200 rpm for10 min. Supernatant was removed and assayed for IL-1β using the OptiEIAkit according to the manufacturer's protocol (Serum may be frozen at−20° C. prior to assay). IC₅₀s were calculated using XLfit.

Example 7 In vivo Assay for Asthma and Lung Function

BALb/cJ mice are immunized with a standard immunization protocol.Briefly, mice (N=8/group) are immunized i.p. with ovalbumin (OVA; 10 μg)in alum on days 0 and 14. Mice are then challenged with aerosolized OVA(5%) on day 21 and 22. Animals receive vehicle (p.o.) or a compound ofthe invention (100 mg/kg p.o.) all starting on day 20.

Lung function is evaluated on day 23 using the Buxco system to measurePenH in response to an aerosol methacholine challenge. Mice are theneuthanized and plasma samples collected at the end of the study.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1. A compound of formula I:

or pharmaceutically acceptable salts thereof, wherein: m is 0 or 1; n is0 or 1; p is from 0 to 4; q is 0 or 1; R¹ is: hydrogen; C₁₋₆alkyl;hydroxy-C₁₋₆alkyl; C₁₋₆alkoxy-C₁₋₆alkyl; hydroxy C₁₋₆alkoxy-C₁₋₆alkyl;or aminocarbonyl-C₁₋₆alkyl; R² is: optionally substituted aryl;optionally substituted heteroaryl; C₃₋₆cycloalkyl; or C₁₋₆alkyl; and R³is: hydrogen; C₁₋₆alkyl; alkylcarbonylalkyl; or alkoxycarbonylalkyl; R⁴and R⁵ each independently is: hydrogen; or C₁₋₆alkyl; each R⁶ isindependently: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl;halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfanyl;C₁₋₆alkylsulfinyl; phenylsulfonyl wherein the phenyl portion isoptionally substituted with C₁₋₆alkyl; nitrile; hydroxy;C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkoxycarbonyl;C₁₋₆alkoxycarbonyl-C₁₋₆alkoxy; hydroxycarbonyl;hydroxycarbonyl-C₁₋₆alkoxy; C₁₋₆alkylaminocarbonyl-C₁₋₆alkoxy;C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylamino-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkoxy; amino; amino-C₁₋₆alkyl; C₁₋₆alkenyl;C₁₋₆alkynyl; morpholinyl; morpholinyl-C₁₋₆alkyl; piperazinyl;piperidinyloxy; aminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxyamino-C₁₋₆alkyl;hydroxy-C₁₋₆alkylamino-C₁₋₆alkyl; C₁₋₆alkoxycarbonylamino-C₁₋₆alkyl;C₁₋₆alkylcarbonylamino-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl;C₁₋₆alkoxycarbonylC₁₋₆alkyl; C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl;C₁₋₆alkylamino-C₁₋₆alkyl; hydroxycarbonyl-C₁₋₆alkyl; hydroxyC₁₋₆alkoxy-C₁₋₆alkyl; or nitro; or two adjacent substituents may form aC₁₋₂alkylenedioxy or halo-C₁₋₂alkylenedioxy; and A is a five or sixmembered heteroaryl ring that is optionally substituted.
 2. The compoundof claim 1, wherein m is
 0. 3. The compound of claim 2, wherein n is 0.3. The compound of claim 2, wherein q is
 0. 4. The compound of claim 3,wherein R¹, R³, R⁴, R⁵ and R′ are hydrogen.
 5. The compound of claim 4,wherein p is 1 or
 2. 6. The compound of claim 5, wherein R¹ is hydrogen.7. The compound of claim 6, wherein R² is optionally substituted phenyl.8. The compound of claim 7, wherein R² is phenyl optionally substitutedone, two or three times with a substituent or substituents eachindependently selected from: fluoro; chloro; bromo; methyl; ethyl;methoxy; ethoxy; trifluoromethyl; difluoromethoxy; nitrile;methoxyethoxy; hydroxyethoxy; hydroxymethyl; hydroxyethyl; orcyclopropylmethoxy.
 9. The compound of claim 7, wherein R² is phenylsubstituted once or twice with a substituent or substituents eachindependently selected from: fluoro; chloro; methyl; methoxy; ornitrile.
 10. The compound of claim 7, wherein R² is phenyl substitutedonce or twice with fluoro.
 11. The compound of claim 7, wherein R² is4-fluoro-phenyl.
 12. The compound of claim 7, wherein R⁶ is: hydrogen;halo; or methyl.
 13. The compound of claim 7, wherein p is 1 and R⁶ ismethyl.
 14. The compound of claim 7, wherein A is a five- orsix-membered heteroaryl selected from: pyrrolyl; pyrazolyl; imidazolyl,pyrrolidinyl, triazolyl; tetrazolyl; oxazolyl; isoxazolyl; thiazolyl;isothiazolyl; thiadiazolyl; oxadiazolyl; oxazolidinyl; pyridinyl;morpholinyl, pyrimidinyl; pyrazinyl; pyridazinyl; or triazinyl, eachoptionally substituted.
 15. The compound of claim 7, wherein A is asix-membered heteroaryl selected from: pyridinyl; triazinyl,pyrimidinyl; pyrazinyl; or pyridazinyl; each optionally substituted onceor twice with methyl; ethyl; propyl; 2-hydroxyethyl; 2-hydroxy-propyl;oxo; 2,3-dihydroxy-propyl; or 2-hydroxy-3-methoxy-propyl.
 16. Thecompound of claim 7, wherein A is a five-membered heteroaryl selectedfrom: pyrrolyl; pyrazolyl; triazolyl; isoxazolyl; oxadiazolyl; oroxazolidinyl, each optionally substituted once or twice with methyl;ethyl; propyl; 2-hydroxyethyl; 2-hydroxy-propyl; 2,3-dihydroxy-propyl;or 2-hydroxy-3-methoxy-propyl.
 17. The compound of claim 7, wherein Ais: pyrrol-1-yl; 1-(2-hydroxy-ethyl) 5-methyl-1H-pyrazol-3-yl;2-methyl-2H-tetrazol-5-yl; 1,5-dimethyl-1H-pyrazol-3-yl;1H-pyrazol-3-yl; 5-methyl-pyridin-2-yl;1-(2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl;2-isobutyl-2H-pyrazol-3-yl; 1-methyl-1H-tetrazol-5-yl;6-methyl-pyridin-3-yl; pyrazol-1-yl;2-(2-hydroxy-ethyl)-5-methyl-2H-pyrazol-3-yl; 2-methyl-2H-pyrazol-3-yl;5-ethyl-2H-pyrazol-3-yl; 4,5-dimethyl-2H-pyrazol-3-yl;3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; 5-ethyl-1H-pyrazol-3-yl1-((R)-2,3-dihydroxy-propyl)-5-methyl-1H-pyrazol-3-yl;2,5-dimethyl-2H-pyrazol-3-yl; 5-methyl-1H-pyrazol-3-yl;5-methyl-1H-[1,2,4]triazol-3-yl; 1,5-dimethyl-1H-[1,2,4]triazol-3-yl; 3methyl-isoxazol-5-yl; 3-methyl-[1,2,4]triazol-1-yl;4-methyl-[1,2,3]triazol-1-yl; 4-methyl-pyrazol-1-yl;5-methyl-[1,3,4]oxadiazol-2-yl; 2-propyl-2H-pyrazol-3-yl;4,5-dimethyl-4H-[1,2,4]triazol-3-yl; 2-oxo-oxazolidin-3-ylmethyl;4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;5-methyl-isoxazol-3-yl; 1-(2-methoxy-ethyl)-5-methyl-1H-pyrazol-3-yl;pyrazin-2-yl; 6-methyl-pyridazin-3-yl; 5-methyl-pyrazin-2-yl;pyrrolidin-1-yl; morpholin-4-yl;4-(2-methoxy-ethyl)-5-methyl-4H-[1,2,4]triazol-3-yl;4-methyl-imidazol-1-yl;1-(ethoxycarbonylmethyl)-5-methyl-1H-pyrazol-3-yl; pyrimidin-2-yl;pyrimidin-5-yl; 2-methyl-pyrimidin-4-yl;5-chloro-3-oxo-2,3-dihydro-pyridazin-4-yl;3-oxo-2,3-dihydro-pyridazin-4-yl; thiazol-4-yl; 2-methyl-thiazol-4-yl;pyridin-4-yl; 4-ethyl-5-methyl-4H-[1,2,4]triazol-3-yl;1-((S)-2,3-dihydroxy-propyl)-5-methyl-1H-pyrazol-3-yl;5-cyclopropyl-1H-pyrazol-3-yl; 1-methyl-1H-pyrazol-3-yl;[1,2,4]triazol-4-yl; 1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl;2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl;3-oxo-2,3-dihydro-pyridazin-4-yl;1-((R)-2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl;1-((S)-2-hydroxy-propyl)-5-methyl-1H-pyrazol-3-yl;1-((R)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl;1-((S)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl;4-((R)-2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;3-methyl-6-oxo-6H-pyridazin-1-yl; 6-methyl-pyrazin-2-yl;4-methyl-pyrimidin-2-yl; 6-oxo-1,6-dihydro-pyrazin-2-yl;5-methyl-1-(hydroxycarbonylmethyl)-1H-pyrazol-3-yl;1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl; 6-oxo-6H-pyridazin-1-yl;2-(2-hydroxy-ethyl)-3-oxo-2,3-dihydro-pyridazin-4-yl;1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl;6-oxo-1,6-dihydro-pyridazin-3-yl; 5-trifluoromethyl-1H-pyrazol-3-yl;2-((R)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl;2-((S)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl;1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-pyrazol-3-yl;2-oxo-1,2-dihydro-pyridin-3-yl; 6-methoxy-pyridazin-3-yl;1-[(2-dimethylamino-ethylcarbamoyl)-methyl]-5-methyl-1H-pyrazol-3-yl;1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl;1-(2-hydroxy-ethyl)-6-oxo-1,6-dihydro-pyridazin-3-yl;5-methyl-2-oxo-2H-pyridin-1-yl; 3-oxo-2,3-dihydro-pyridazin-4-yl;2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl;1-((R)-2-hydroxy-3-methoxy-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl;1-((S)-2-hydroxy-3-methoxy-propyl)-6-oxo-1,6-dihydro-pyridazin-3-yl;5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl;4-ethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl;4-methyl-6-oxo-6H-pyridazin-1-yl;1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl;1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl;1-((R)-2-hydroxy-3-methoxy-propyl)-2-oxo-1,2-dihydro-pyridin-3-yl; or1-(2-acetoxy-3-methoxy)-propyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl.18. The compound of claim 7, wherein A is:1-(2-hydroxy-ethyl)-5-methyl-1H-pyrazol-3-yl;3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl; 5-methyl-1H-pyrazol-3-yl;4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;4-(2-hydroxy-ethyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;3-oxo-2,3-dihydro-pyridazin-4-yl;2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl;3-oxo-2,3-dihydro-pyridazin-4-yl;1-((R)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl;1-((S)-2-hydroxy-3-methoxy-propyl)-5-methyl-1H-pyrazol-3-yl;4-((R)-2-hydroxy-3-methoxy-propyl)-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl;1-(2-hydroxy-ethyl)-1H-pyrazol-3-yl;2-(2-hydroxy-ethyl)-3-oxo-2,3-dihydro-pyridazin-4-yl;2-((R)-2-hydroxy-3-methoxy-propyl)-3-oxo-2,3-dihydro-pyridazin-4-yl;2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl; or4-ethyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl.
 19. The compoundof claim 1, wherein said compound is of formula II:

wherein: p is from 0 to 3; R⁶ is: hydrogen; C₁₋₆alkyl; or halo; R⁷ is:hydrogen; halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl; halo-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl; C₁₋₆alkylsulfanyl; C₁₋₆alkylsulfinyl; phenylsulfonylwherein the phenyl portion is optionally substituted with C₁₋₆alkyl;nitrile; hydroxy; C₁₋₆alkylcarbonyl; aminocarbonyl; C₁₋₆alkoxycarbonyl;C₁₋₆alkoxycarbonyl-C₁₋₆alkoxy; hydroxycarbonyl;hydroxycarbonyl-C₁₋₆alkoxy; C₁₋₆alkylaminocarbonyl-C₁₋₆alkoxy;C₁₋₆alkoxy-C₁₋₆alkoxy; hydroxy-C₁₋₆alkoxy; C₁₋₆alkylamino-C₁₋₆alkoxy;C₁₋₆alkylsulfonyl-C₁₋₆alkoxy; hydroxy-C₁₋₆alkyl;C₃₋₆cycloalkyl-C₁₋₆alkoxy; amino; amino-C₁₋₆alkyl; C₁₋₆alkenyl;C₁₋₆alkynyl; morpholinyl; morpholinyl-C₁₋₆alkyl; piperazinyl;piperidinyloxy; aminocarbonyl-C₁₋₆alkoxy; C₁₋₆alkoxyamino-C₁₋₆alkyl;hydroxy-C₁₋₆alkylamino-C₁₋₆alkyl; C₁₋₆alkoxycarbonylamino-C₁₋₆alkyl;C₁₋₆alkylcarbonylamino-C₁₋₆alkyl; C₁₋₆alkylaminocarbonyl;C₁₋₆alkoxycarbonylC₁₋₆alkyl; C₁₋₆alkylaminocarbonyl-C₁₋₆alkyl;C₁₋₆alkylamino-C₁₋₆alkyl; hydroxycarbonyl-C₁₋₆alkyl; or nitro; each R¹¹independently is: halo; C₁₋₆alkyl; C₁₋₆alkoxy; halo-C₁₋₆alkyl;halo-C₁₋₆alkoxy; C₁₋₆alkylsulfonyl; or nitrile; and A and R^(a) are asrecited in claim
 1. 20. The compound of claim 19, wherein r is 1 and R¹¹is halo.
 21. The compound of claim 20, wherein R⁷ is hydrogen.
 22. Thecompound of claim 21, wherein R⁶ is methyl.
 23. A compositioncomprising: (a) a pharmaceutically acceptable carrier; and (b) acompound of claim
 1. 24. A method for treating arthritis, said methodcomprising administering to a subject in need thereof an effectiveamount of a compound of claim 1.